dizocilpine-maleate and Seizures

In this review article, we describe the unrecognized roles of glutamate and glutamate receptors in malignant glioma biology. The neurotransmitter glutamate released from malignant glioma cells in the extracellular matrix is responsible for seizure induction and at higher concentration neuronal cell death. This neuronal cell death will create vacated place for tumor growth. Glutamate also stimulates the growth and the migration of glial tumor cells by means of the activation of glutamate receptors on glioma cells in a paracrine and autocrine manner. The multitude of effects of glutamate in glioma biology supports the rationale for pharmacological targeting of glutamate receptors and transporters in the adjuvant treatment of malignant gliomas in neurology and neuro-oncology. Using the website www.clinicaltrials.gov/ as a reference - a service developed by the National Library of Medicine for the National Health Institute in USA - we have evoked the few clinical trials completed and currently ongoing with therapies targeting the glutamate receptors.

Topics: Benzodiazepines; Brain Neoplasms; Cell Death; Cell Movement; Cell Proliferation; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glioma; Glutamic Acid; Humans; Memantine; Neoplasm Invasiveness; Neuroglia; Neurons; Receptors, AMPA; Receptors, Glutamate; Seizures; Sulfasalazine

Topics: Animals; Biological Transport, Active; Brain; Calcium; Dizocilpine Maleate; Humans; Interleukin-1; Receptors, N-Methyl-D-Aspartate; Seizures

Perinatal asphyxia is associated with an increased risk of cerebral palsy and significant mortality. We investigated the use of flunarizine, a calcium antagonist and MK-801, an excitatory amino acid antagonist, in preventing the sequelae of severe hypoxic/ischemic insults. Flunarizine was neuroprotective in the infant rat subjected to unilateral carotid ligation and 2 h of hypoxia. Preliminary analysis of experiments in a novel model of cerebral ischemia in the fetal sheep suggests that prophylactic treatment with flunarizine greatly modified the outcome after 30 min of total ischemia. Treatment with MK-801 prevented post-ischemic seizures. The background to these developments is outlined and future prospects considered.

Topics: Animals; Anticonvulsants; Dibenzocycloheptenes; Disease Models, Animal; Dizocilpine Maleate; Female; Fetal Diseases; Flunarizine; Hypoxia, Brain; Pregnancy; Rats; Seizures; Sheep

The effects of a single and multiple doses of ginkgolide A, B, C, and bilobalide, active components of Ginkgo biloba extract (EGb 761), on absence seizures were investigated in male WAG/Rij rats, a genetic animal model of absence epilepsy. Furthermore, the interactions of ginkgolide A together with NMDA receptor antagonist MK-801, AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), or L-type calcium channel blocker nicardipine were studied to figure out how ginkgolide A affects spike-wave discharges (SWDs) in the brain. The experiments were done using 6-8-month-old male WAG/Rij rats with infusion cannula and EEG electrode implanted. Ginkgolide A, B, C, and bilobalide were administered intraperitoneally for 7 days at a dose of 6 mg/kg. In interaction groups, 6 μg ginkgolide A was injected intracerebroventricularly in combination with MK-801 (10 μg), CNQX (1 μg), and nicardipine (50 μg) for 7 days. EEG was recorded from animals at the baseline, first dose, and seventh dose periods for 4 h. Ginkgolide A (p = .028), C (p = .046), and bilobalide (p = .043) significantly increased the frequency of SWDs in WAG/Rij rats. Ginkgolide A injected into the lateral ventricle with MK-801 (p = .046), CNQX (p = .043), and nicardipine (p = .046) significantly increased the number of SWDs after seventh dose. Finally, the EGb 761-related increase in absence epilepsy was determined to be caused by ginkgolide A, C, and bilobalide. All three receptor antagonists/channel blockers do not inhibit the pro-absence effect of ginkgolide A. The findings revealed that ginkgolide A's pro-absence effect is mediated by brain circuits other than ionotropic glutamate receptors or L-type calcium channels.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Bilobalides; Disease Models, Animal; Dizocilpine Maleate; Electroencephalography; Epilepsy, Absence; Excitatory Amino Acid Antagonists; Ginkgolides; Male; Nicardipine; Rats; Seizures

Allopurinol, a uric-acid-lowering medication, has shown its efficacy in several studies suggesting that allopurinol can be prescribed as adjunctive cure meant for intractable epilepsy. The exact mechanism of allopurinol is still unknown. This study evaluates allopurinol's effect on seizure threshold, seizure incidence, and mortality rate in mice models. Moreover, the possible involvement of nitric oxide (NO) pathway and N-methyl-D-aspartate (NMDA) receptors are investigated. To evaluate the effect of allopurinol on seizure, we used the pentylenetetrazole (PTZ)-induced seizure along with maximal electroshock (MES)-induced seizure. To assess the underlying mechanism behind the allopurinol activity, we used nitric oxide synthase (NOS) substrate (L-arginine), NOS inhibitors (L-NAME, aminoguanidine, 7-nitroindazole), and NMDA receptor antagonist (MK-801). Intraperitoneal allopurinol administration at a dose of 50 mg/kg in mice showed a significant (p < 0.001) anti-convulsant activity in the PTZ-induced seizure. Even though pre-treatment with L-Arginine (60 mg/kg) potentiates allopurinol's anti-convulsant effect in the PTZ-induced seizure, pre-treatment with L-NAME (10 mg/kg), aminoguanidine (100 mg/kg), and 7-nitroindazole (30 mg/kg) reversed the anti-convulsant effect of allopurinol in the PTZ-induced seizure. In addition, pre-treatment with MK-801 also decreased the anti-convulsant effect of allopurinol in the PTZ-induced seizure. While allopurinol at a dose of 50 mg/kg and 100 mg/kg did not induce protection against seizure incidence in the MES-induced seizure, it revealed a remarkable effect in reducing the mortality rate in the MES-induced seizure. Allopurinol increases the seizure threshold in PTZ-induced seizure and enhances the survival rate in MES-induced seizure. Allopurinol exerts its anti-convulsant effect, possibly through targeting NO pathway and NMDA receptors.

Topics: Allopurinol; Animals; Anticonvulsants; Arginine; Convulsants; Dizocilpine Maleate; Electroshock; Enzyme Inhibitors; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pentylenetetrazole; Receptors, N-Methyl-D-Aspartate; Seizures

Data on the long-term consequences of a single episode of generalized seizures in infants are inconsistent. In this study, we examined the effects of pentylenetetrazole-induced generalized seizures in three-week-old rats. One month after the seizures, we detected a moderate neuronal loss in several hippocampal regions: CA1, CA3, and hilus, but not in the dentate gyrus. In addition, long-term synaptic potentiation (LTP) was impaired. We also found that the mechanism of plasticity induction was altered: additional activation of metabotropic glutamate receptors (mGluR1) is required for LTP induction in experimental rats. This disturbance of the plasticity induction mechanism is likely due to the greater involvement of perisynaptic NMDA receptors compared to receptors located in the core part of the postsynaptic density. This hypothesis is supported by experiments with selective blockades of core-located NMDA receptors by the use-dependent blocker MK-801. MK-801 had no effect on LTP induction in experimental rats and suppressed LTP in control animals. The weakening of the function of core-located NMDA receptors may be due to the disturbed clearance of glutamate from the synaptic cleft since the distribution of the astrocytic glutamate transporter EAAT2 in experimental animals was found to be altered.

Topics: Animals; Dizocilpine Maleate; Hippocampus; Neuronal Plasticity; Pentylenetetrazole; Rats; Receptors, N-Methyl-D-Aspartate; Seizures

Mechanism of ictogenesis of D- and L-stereroisomers of homocysteic acid was studied in 12-day-old rats by means of antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. There was no qualitative difference between the two stereoisomers in generation of emprosthotonic (flexion) as well as generalized tonic-clonic seizures. Moderate differences were observed in the first, nonconvulsive effects of the two isomers. As generation of the two types of seizures is concerned, NMDA and AMPA participate in generalized tonic-clonic seizures whereas NMDA receptors play a dominant role in generation of flexion seizures.

Topics: 2-Amino-5-phosphonovalerate; Animals; Benzodiazepines; Dizocilpine Maleate; Homocysteine; Male; Quinoxalines; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Seizures; Stereoisomerism

Methadone is a synthetic opioid used to treat opiate withdrawal and addiction. Studies have demonstrated the impact of methadone on seizure susceptibility. This study investigated the modulatory impacts of acute and subchronic (three times daily for 5 days) intraperitoneal methadone treatment on pentylenetetrazole-induced clonic seizure threshold (CST) in mice, as well as the involvement of the nitric oxide, N-methyl-d-aspartate (NMDA), and µ-opioid pathways. Acute administration of different doses of methadone (0.1, 0.3, 1, and 3 mg/kg) 45 min before CST significantly decreased the seizure threshold. Additionally, pretreatment with noneffective doses of an opioid receptor antagonist (naltrexone) and NMDA receptor antagonists (ketamine and MK-801) inhibited methadone's proconvulsive activity in the acute phase, while l-NAME (a nonspecific nitric oxide synthase (NOS) inhibitor) did not affect that activity. In the subchronic phase, methadone (3 mg/kg) demonstrated an anticonvulsive effect. Although subchronic pretreatment with noneffective doses of l-NAME and 7-nitroindazole (a specific neuronal NOS inhibitor) reversed methadone's anticonvulsive activity, aminoguanidine (a specific inducible NOS inhibitor), naltrexone, MK-801, and ketamine did not change methadone's anticonvulsive characteristic. Our results suggest that NMDA and µ-opioid receptors may be involved in methadone's proconvulsive activity in the acute phase, while methadone's anticonvulsive activity may be modulated by neuronal NOS in the subchronic phase.

Topics: Animals; Anticonvulsants; Dizocilpine Maleate; Guanidines; Indazoles; Ketamine; Male; Methadone; Mice; Naltrexone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pentylenetetrazole; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Seizures

The underlying mechanisms for the neuroprotective effects of lithium chloride in neurodegenerative diseases such as seizures remain unknown. In present study the downstream signaling pathway of phospho-ERK/NMDA receptors/nitric oxide has been studied. For this purpose, acute and chronic effect of lithium in seizure animal model and the interaction of NMDA receptor antagonist (MK-801) and neuronal nitric oxide synthase (nNOS) inhibitor (7-NI) with these neuroprotection has been studied. Acute lithium administration showed pro-convulsive properties in pentylenetetrazole (PTZ)-induced seizure model while chronic treatment increased the seizure threshold significantly. The serum level of lithium in treated mice were 0.48 mEq/L corresponding the therapeutic range. Administration of 7-NI (30mg/kg, i.p.) and MK-801 (0.001mg/kg, i.p.) had no effect on seizure threshold, while co-administration of them before the sub-effective dose of lithium (4mg/kg, i.p.) increased the anticonvulsant effect of lithium significantly. Furthermore, acute injection of MK-801 (0.05mg/kg) or 7-NI (60mg/kg) and co-administration of them significantly suppressed the anticonvulsant effect of effective dose of lithium (10mg/kg). This data demonstrated involvement of NMDA receptors/nitric oxide pathway in anticonvulsant effect of lithium. In cerebellar granule neurons (CGNs) culture studies on glutamate excitotoxicity western blot analysis, nitrite assay by Griess reaction, cell viability and microscopic morphology evaluation has been carried out to find the role of NMDA receptor/nitric oxide and phospho-ERK signaling in lithium neuroprotection. Using MTT assay and morphologic examinations, chronic lithium treatment showed protective effects against glutamate toxicity in primary cerebellar culture neurons. The level of nitric oxide was significantly reduced in co-administration of lithium and glutamate while glutamate significantly increased levels of nitric oxide. The involvement of NMDA receptors/nitric oxide and phospho-ERK pathway in the effects of lithium on cerebellar neurons has been shown. Inhibition of ERK signaling may be reconsidered as a pharmacological approach for seizure control.

Topics: Animals; Anticonvulsants; Cells, Cultured; Cerebellum; Cerebral Cortex; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Lithium Chloride; Male; MAP Kinase Signaling System; Mice; Neurons; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase Type I; Pentylenetetrazole; Phosphorylation; Receptors, N-Methyl-D-Aspartate; Seizures

Pentylenetetrazole (PTZ) is one of the most valuable drugs used to induce seizure-like state in zebrafish especially considering the pharmacological screening for anticonvulsants and the study of basic mechanisms of epilepsy. Here, the effect of gender, weight and changes in temperature on latency to adult zebrafish reach classical seizure states induced by PTZ (10mM) was evaluated. Gender and weight (200-250mg versus 400-500mg) did not affect the profile of response to PTZ. When water temperature was changed from 22 to 30°C the lower temperature increased the latency time to reach seizure states and the higher temperature significantly decreased it, in comparison to the control group maintained at 26°C. The blockage of kainate receptors by DNQX (10μM) were unable to prevent the increased susceptibility of adult zebrafish exposed to hyperthermia and PTZ-induced seizures. The NMDA block by MK-801 (2.5μM) prevented the additive effect of hyperthermia on PTZ effects in adult zebrafish. This report emphasize that PTZ model in adult zebrafish exhibits no confounder factors from gender and weight, but water temperature is able to directly affect the response to PTZ, especially through a mechanism related to NMDA receptors.

Topics: Animals; Anticonvulsants; Body Weight; Convulsants; Dizocilpine Maleate; Female; Fever; Male; Models, Animal; Neurotransmitter Agents; Pentylenetetrazole; Seizures; Sex Characteristics; Temperature; Water; Zebrafish

Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine-like opioid. When administered at supra-antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well-documented, few studies have examined the effects of high-dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80mg/kg), Sprague-Dawley rats showed increased seizure occurrence and intensity. Hippocampal expression levels of N-methyl-d-aspartate (NMDA) receptor subunits (GluN1

Topics: Animals; Antitussive Agents; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

Experiencing psychosocial stress in early life, such as social isolation stress (SIS), is known to have negative enduring effects on the development of the brain and behavior. In addition to anxiety and depressive-like behaviors, we previously showed that juvenile SIS increases susceptibility to pentylenetetrazole (PTZ)-induced seizures in mice through enhancing the nitrergic system activity in the hippocampus. In this study, we investigated the possible involvement of N-methyl-D-aspartate (NMDA) receptors in proconvulsant effects of juvenile SIS. Applying 4 weeks of SIS to juvenile male mice at postnatal day 21-23, we observed an increased susceptibility to PTZ as well as anxiety and depressive-like behaviors in adult mice. Intraperitoneal (i.p.) administration of NMDA receptor antagonists, MK-801 (0.05 mg/kg) and ketamine (0.5mg/kg), reversed the proconvulsant effects of SIS in Isolated (and not social) housed animals. Co-administration of non-effective doses of nitric oxide synthase (NOS) inhibitors, 7NI (25mg/kg) and L-NAME (10mg/kg), with NMDA receptor antagonists, MK-801 (0.01 mg/kg) and ketamine (0.1mg/kg) attenuated the proconvulsant effects of juvenile SIS only in isolated housed mice. Also, using real time RT-PCR, we showed that hippocampal upregulation of NR2B subunit of NMDA receptor may play a critical role in proconvulsant effects of juvenile SIS by dysregulation of NMDA/NO pathway. In conclusion, results of present study revealed that experiencing SIS during adolescence predisposes the co-occurrence of seizure disorders with psychiatric comorbidities and also, alteration of NMDA receptor structure and function in hippocampus plays a role in proconvulsant effects of juvenile SIS through enhancing the NMDA/NO pathway.

Topics: Age Factors; Animals; Animals, Newborn; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Immobility Response, Tonic; Indazoles; Ketamine; Male; Maze Learning; Mice; Motivation; NG-Nitroarginine Methyl Ester; Pentylenetetrazole; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Seizures; Social Isolation; Statistics, Nonparametric; Swimming; Time Factors

Treatment of depression, a common comorbidity in patients with epilepsy, is restricted as certain antidepressants are considered to be proconvulsants. In contrast, anticonvulsant effects have been reported with some antidepressants. In the present study, the effect of tianeptine, an antidepressant, was evaluated against pentylenetetrazole (PTZ)-induced seizures, cognitive impairment and oxidative stress in rats. Tianeptine was administered in three doses (20, 40 and 80 mg/kg) 30 min before PTZ (60 mg/kg, intraperitoneally). MK801, an N-methyl-D-aspartate antagonist, and naloxone, an opioid receptor antagonist, were administered with tianeptine to evaluate the involvement of N-methyl-D-aspartate and opioid receptors, respectively. Morris water maze, elevated plus maze and passive avoidance tests were performed for behavioural assessment. Brain malondialdehyde and reduced glutathione levels were estimated as markers of oxidative stress. Tianeptine showed dose-dependent protection against PTZ seizures. Coadministration of tianeptine with MK801 potentiated the anticonvulsant effect of tianeptine. The protective effect of tianeptine against PTZ seizures was mitigated when tianeptine was administered with naloxone. Impairment of learning and memory by PTZ was prevented by tianeptine. Tianeptine also attenuated the seizure-induced increased oxidative stress. Thus, tianeptine showed an anticonvulsant effect along with amelioration of seizure-induced cognitive impairment and oxidative stress. Hence, tianeptine could be a useful drug in epileptic patients with depression, with the advantage of having both antidepressant and antiepileptic effects.

Topics: Animals; Anticonvulsants; Antidepressive Agents, Tricyclic; Avoidance Learning; Behavior, Animal; Cognitive Dysfunction; Dizocilpine Maleate; Dose-Response Relationship, Drug; Glutathione; Male; Malondialdehyde; Maze Learning; Naloxone; Oxidative Stress; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Thiazepines

3,4-Methylenedioxy-methamphetamine (MDMA) is a unique psychostimulant that continues to be a popular drug of abuse. It has been well documented that MDMA reduces markers of 5-HT axon terminals in rodents, as well as humans. A loss of parvalbumin-immunoreactive (IR) interneurons in the hippocampus following MDMA treatment has only been documented recently. In the present study, we tested the hypothesis that MDMA reduces glutamic acid decarboxylase (GAD) 67-IR, another biochemical marker of GABA neurons, in the hippocampus and that this reduction in GAD67-IR neurons and an accompanying increase in seizure susceptibility involve glutamate receptor activation. Repeated exposure to MDMA (3×10mg/kg, ip) resulted in a reduction of 37-58% of GAD67-IR cells in the dentate gyrus (DG), CA1, and CA3 regions, as well as an increased susceptibility to kainic acid-induced seizures, both of which persisted for at least 30days following MDMA treatment. Administration of the NMDA antagonist MK-801 or the glutamate transporter type 1 (GLT-1) inducer ceftriaxone prevented both the MDMA-induced loss of GAD67-IR neurons and the increased vulnerability to kainic acid-induced seizures. The MDMA-induced increase in the extracellular concentration of glutamate in the hippocampus was significantly diminished in rats treated with ceftriaxone, thereby implicating a glutamatergic mechanism in the neuroprotective effects of ceftriaxone. In summary, the present findings support a role for increased extracellular glutamate and NMDA receptor activation in the MDMA-induced loss of hippocampal GAD67-IR neurons and the subsequent increased susceptibility to evoked seizures.

Topics: Animals; Body Temperature; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Gene Expression Regulation; Glutamate Decarboxylase; Glutamic Acid; Hallucinogens; Hippocampus; Kainic Acid; Male; Microdialysis; N-Methyl-3,4-methylenedioxyamphetamine; Neurons; Rats; Rats, Sprague-Dawley; Seizures; Up-Regulation

Identification of new molecular targets as well as the new models recapitulating different aspects of pathophysiology of status epilepticus (SE) in humans might prove essential for the breakthrough in the efforts against pharmacoresistance in epilepsy. Recently, we described a new model of generalized convulsive SE induced with orphenadrine (ORPH) in rats with unique characteristics [5]. The current study was aimed at assessing the efficacy of a new generation antiepileptic drugs (AEDs) and some of the experimental agents in suppressing ORPH-evoked seizures in rats.. ORPH was administered intraperitoneally (ip) in the dose of 80 mg/kg in male Wistar rats. The latency to first seizure, the number of seizure episodes and the duration of overt SE, as well as the incidence of deaths was scored with simultaneous electroencephalographic (EEG) recordings.. ORPH induced seizures in 100% of animals at a dose of 80 mg/kg, associated with low mortality and good behavioural outcome. Among new generation AEDs: felbamate, levetiracetam, topiramate, lamotrigine and progabide did not affect the seizure incidence. Among the experimental drugs, only dizocilpine, the non-competitive NMDA antagonist, dose-dependently affected the occurrence of the SE (p<0.001). However, CGP-39551 competitive NMDA antagonist, the same as scopolamine and mecamylamine (muscarinic and nicotinic receptors antagonists, respectively) showed no effect.. Based on the above findings, one may speculate that NMDA activation is partly involved in the proconvulsant activity of orphenadrine but may not be the primary pathomechanism. ORPH-induced seizures may provide an interesting option for studying novel targets for pharmacological interventions in status epilepticus.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Dizocilpine Maleate; Electroencephalography; Hippocampus; Male; N-Methylaspartate; Orphenadrine; Rats; Rats, Wistar; Seizures; Status Epilepticus

Seizure causes autonomic, neuroendocrine and stress responses. We examined the effects of kainic acid (KA)-induced seizures on the expression of the arginine vasopressin (AVP)-enhanced green fluorescent protein (eGFP) in the locus coeruleus (LC), an area known to contain noradrenergic cells, in AVP-eGFP transgenic male and female rats, with the rationale to identify stressors which induce AVP synthesis in the LC. Subcutaneous (s.c.) administration of KA caused a progressive development of seizure behavior within 24 h. AVP-eGFP fluorescence in the LC was detected 6, 24, and 48 h and 1 week after administration of KA (12 mg/kg). From a nearly undetectable level, it reached a maximum at 48 h after s.c. administration of KA and returned to the basal levels after 2 weeks. AVP-eGFP fluorescence in the LC after s.c. administration of KA was significantly reduced by the pretreatment with MK-801 (nonselective N-methyl-D-aspartate (NMDA) receptor antagonist). In the KA-administered rats, immunohistochemistry for tyrosine hydroxylase (TH) revealed that the eGFP fluorescence was co-localized with TH-immuno-reactivity in the LC. These results suggest that the synthesis of AVP-eGFP is potentially up-regulated in noradrenergic neurons in the LC after KA-induced seizures through the activation of NMDA receptors.

Topics: Animals; Animals, Genetically Modified; Arginine Vasopressin; Dizocilpine Maleate; Female; Green Fluorescent Proteins; Kainic Acid; Locus Coeruleus; Male; Rats; Rats, Wistar; Recombinant Fusion Proteins; Seizures; Tyrosine 3-Monooxygenase; Up-Regulation

Considering the putative participation of N-methyl-D-aspartate (NMDA) receptors and the Na(+), K(+)-ATPase enzymes in the susceptibility to convulsions induced by the benzodiazepine inverse agonist methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), the present study sought to determine if rats with high (HTR) and low (LTR) thresholds to clonic convulsions induced by DMCM differed in the following aspects: the binding of NMDA receptors by [(3)H]-MK-801, Na(+), K(+)-ATPase activity (K(+)-stimulated p-nitrophenylphosphatase) and high-affinity [(3)H]-ouabain binding to membranes from discrete brain regions. Compared to the HTR subgroup, the LTR subgroup presented a lower binding of [(3)H]-MK-801 in the hippocampus, frontal cortex and striatum. The subgroups did not differ in K(+)-p-nitrophenylphosphatase activity, but the LTR subgroup had a lower density of isozymes with a high-affinity to ouabain in the brainstem and in the frontal cortex and a lower affinity to ouabain in the hippocampus than the HTR subgroup. These results suggest that NMDA receptors and ouabain-sensitive Na(+), K(+)-ATPase isozymes may underlie the susceptibility to DMCM-induced convulsions.

Topics: Animals; Brain; Carbolines; Dizocilpine Maleate; Male; Ouabain; Radioligand Assay; Rats; Rats, Wistar; Seizures; Tritium

Pharmacological control of seizure activity following nerve agent exposure is critical in reducing neuropathology and improving survival in casualties. Three classes of drugs, anticholinergics, benzodiazepines and excitatory amino acid (EAA) antagonists, have been shown to be effective at moderating nerve agent-induced seizures. However, little is known about which brain structures are involved in producing the anticonvulsant response. This study evaluated drugs from each class, injected directly into one of three specific brain structures, the perirhinal cortex, the entorhinal cortex, or the mediodorsal thalamus, for their ability to modulate seizures induced by the nerve agent soman. The drugs evaluated were the anticholinergic scopolamine, the benzodiazepine midazolam, and the EAA antagonist MK-801. For each drug treatment in each brain area, anticonvulsant ED₅₀ values were calculated using an up-down dosing procedure over successive animals. There was no statistical difference in the anticonvulsant ED₅₀ values for scopolamine and MK-801 in the perirhinal and entorhinal cortices. MK-801 pretreatment in the mediodorsal thalamus had a significantly lower anticonvulsant ED₅₀ value than any other treatment/injection site combination. Midazolam required significantly higher doses than scopolamine and MK-801 in the perirhinal and entorhinal cortices to produce an anticonvulsant response and was ineffective in the mediodorsal thalamus. These findings support the contention that specific neuroanatomical pathways are activated during nerve agentinduced seizures and that the discrete brain structures involved have unique pharmacological thresholds for producing an anticonvulsant response. This study is also the first to show the involvement of the mediodorsal thalamus in the control of nerve agent-induced seizures.

Topics: Animals; Anticonvulsants; Brain; Brain Mapping; Chemical Warfare Agents; Cholinergic Antagonists; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroencephalography; Excitatory Amino Acid Antagonists; Male; Midazolam; Rats; Rats, Sprague-Dawley; Scopolamine; Seizures; Soman

Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic-clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4mg/kg was 100% lethal. The NMDA antagonist, ketamine (35mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic-clonic seizures or lethality, but increased the number of clonic seizures. Doubling the ketamine dose decreased tonic-clonic seizures and eliminated lethality through a 60min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABA(A) receptor allosteric enhancer diazepam (5mg/kg) greatly reduced seizure manifestations and prevented lethality 60min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists is more likely to be effective in treating TMDT poisoning.

Topics: Animals; Anticonvulsants; Convulsants; Diazepam; Dizocilpine Maleate; Electroencephalography; Excitatory Amino Acid Antagonists; Ketamine; Male; Mice; Mice, Inbred C57BL; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Rodenticides; Seizures; Sesquiterpenes

We studied parameters of specific receptor binding of D2-dopamine receptor ligand [(3)H]-sulpiride and NMDA-receptor ligand [(3)H]-MK-801 on the membranes of striatum cells in Krushinsky-Molodkina rats (predisposed to audiogenic seizures) and strain "0" selected for the absence of audiogenic seizures. No interstrain differences were observed in affinity (K(d)) of both D2- and NMDA-receptors to ligands. At the same time, significant interstrain differences in receptor density (B(max)) were found for both D2-receptors and NMDA-receptors. The reduced number of dopamine and glutamate receptors in the striatum can be associated with neurological peculiarities of Krushinsky-Molodkina rat strain (audiogenic seizures and postictal catalepsy).

Topics: Animals; Binding Sites; Corpus Striatum; Dizocilpine Maleate; Male; Protein Binding; Rats; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Seizures

Glutamate is the major excitatory neurotransmitter of the central nervous system in vertebrates. Excitotoxicity, caused by over-stimulation of the glutamate receptors, is a major cause of neuron death in several brain diseases, including epilepsy. We describe here how behavioural seizures can be triggered in adult zebrafish by the administration of kainate and are very similar to those observed in rodent models. Kainate induced a dose-dependent sequence of behavioural changes culminating in clonus-like convulsions. Behavioural seizures were suppressed by DNQX (6,7-dinitroquinoxaline-2,3-dione) dose-dependently, whilst MK-801 (a non-competitive NMDA receptor antagonist) had a lesser effect. Kainate triggers seizures in adult zebrafish, and thus this species can be considered as a new model for studying seizures and subsequent excitotoxic brain injury.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Kainic Acid; Quinoxalines; Rats; Receptors, Glutamate; Seizures; Zebrafish

The aim of our study was to investigate the effects of ifenprodil and MK-801 on D,L-homocysteine thiolactone induced seizures in adult rats.Male Wistar rats were divided into following groups: 1. Saline-treated (C, n=10); 2. D,L-homocysteine thiolactone 8 mmol/kg, i.p. (H, n=7); 3. Ifenprodil 20 mg/kg i.p. (IF, n=8); 4. MK-801 0.5 mg/kg, i.p. (MK, n=8) and 5. Groups that received IF or MK 30 minutes prior to H (IFH, n=8 and MKH, n=8). Seizure behavior was assessed by incidence, latency, number and intensity of seizure episodes. Seizure severity was described by a descriptive scale with grades 0-4. Lethality in experimental group was recorded 90 min and 24 h upon D,L-homocysteine thiolactone administration.There were no behavioral signs of seizure activity in groups C, IF and MK.Pre-treatment with MK-801 (MKH) showed tendency to reduced incidence of convulsions, latency to the first seizure onset and the severity of seizure episodes, but statistical significance was not attained comparing to the H group. However, median number of seizure episodes was significantly decreased in MKH (p<0.05), comparing to the H group. On the other hand, ifenprodil (IFH) decreased the latency to the first seizure onset and increased the median number of seizure episodes (p<0.05). The majority of seizure episodes in IFH (72.1%, p<0.05) and MKH (73.1%, p<0.05) groups was grade 2 and significantly different comparing to the H (36.0%). Our findings suggest that MK-801 has a mild anticonvulsive effect on D,L-homocysteine thiolactone induced seizures in adult rats.

Topics: Animals; Dizocilpine Maleate; Homocysteine; Male; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

Theophylline-associated convulsions are frequently exacerbated by fever, but the mechanisms behind it are still not completely understood. We investigated whether N-methyl-D-aspartic acid (NMDA) and gamma aminobutyric acid (GABA) receptors are involved in aminophylline (theophylline-2-ethylenediamine)-induced convulsions that are augmented by heat exposure-induced hyperthermia in mice. Mice exposed to 33 °C temperatures for 2 h had significantly increased body temperature (0.94 °C). Heat exposure significantly decreased time required for the onset of convulsions induced by an intraperitoneal (i.p.) injection of aminophylline (300 mg/kg). The shortened time for onset of convulsions was blocked by the NMDA receptor antagonist dizocilpine (0.1, 0.3 mg/kg, i.p.). However, the GABA(A) receptor agonist muscimol (1, 2 mg/kg, i.p.) did not have any effect. The pro-convulsant action of NMDA (100-125 mg/kg, i.p.) was enhanced by the heat exposure of 33 °C. However, the pro-convulsant actions of picrotoxin (3-4 mg/kg, i.p.), a GABA(A) receptor antagonist, were not affected by increased temperatures. These results suggest that NMDA receptors in the brain play a role in aminophylline-induced convulsions, which are augmented by heat exposure-induced hyperthermia in mice.

Topics: Aminophylline; Animals; Dizocilpine Maleate; Fever; Male; Mice; Muscimol; Seizures; Theophylline

The ability of MK-801 (dizocilpine), a noncompetitive N-methyl D-aspartate (NMDA) antagonist, to antagonize electrical seizures is reduced in stressed mice. Stress-associated alterations in seizure susceptibility and diminished efficacy of antiseizure medications in humans have been reported [Joëls, 2009; Haut et al., 2007; Moshe et al., 2008]; thus, these experimental observations implicate altered endogenous tone of NMDA receptor-mediated neurotransmission in clinically adverse effects of stress on seizure proneness and treatment. The current exploratory experiment examined the effect of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an antagonist of mGluR5, administered prior to stress on the stress-induced reduction of MK-801's antiseizure effect in Swiss-Webster and Balb/c mice; the Balb/c mouse is behaviorally hypersensitive to MK-801. Interestingly, the data suggest that MPEP can attenuate the severity of the stress-induced reduction of MK-801's antiseizure effect in the Balb/c strain. Thus, mGluR5 could serve as a target for strategies for adjuvant treatment of seizures exacerbated by stress.

Topics: Animals; Dizocilpine Maleate; Electroshock; Male; Mice; Mice, Inbred BALB C; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Seizures; Stress, Physiological; Stress, Psychological

Recurrent seizure activity has been shown to induce a variety of permanent structural changes in the brain. Matrix metalloproteinases (MMPs) function to promote neuronal plasticity, primarily through cleavage of extracellular matrix proteins. Here, we investigated the role of MMP-9 in the development of pentylenetetrazole (PTZ)-induced kindled seizure in mice. Repeated treatment with PTZ (40 mg/kg) produced kindled seizure, which was accompanied by enhanced MMP-9 activity and expression in the hippocampus. No change in MMP-9 activity was observed in the hippocampi of mice with generalized tonic seizure following single administration of PTZ (60 mg/kg). MMP-9 colocalized with the neuronal marker NeuN and the glial marker GFAP in the dentate gyrus of the kindled mouse hippocampus. Coadministration of diazepam or MK-801 with PTZ inhibited the development of kindling and the increased MMP-9 levels in the hippocampus. Marked suppression of kindled seizure progression in response to repeated PTZ treatment was observed in MMP-9((-/-)) mice compared with wild-type mice, an observation that was accompanied by decreased hippocampal levels of mature brain-derived neurotrophic factor. Microinjecting the BDNF scavenger TrkB-Fc into the right ventricle before each PTZ treatment significantly suppressed the development of kindling in wild-type mice, whereas no effect was observed in MMP-9((-/-)) mice. On the other hand, bilateral injections of pro-BDNF into the hippocampal dentate gyrus significantly enhanced kindling in wild-type mice but not MMP-9((-/-)) mice. These findings suggest that MMP-9 is involved in the progression of behavioral phenotypes in kindled mice because of conversion of pro-BDNF to mature BDNF in the hippocampus.

Topics: Animals; Anticonvulsants; Blotting, Western; Brain-Derived Neurotrophic Factor; Convulsants; Diazepam; Dizocilpine Maleate; Electrophoresis, Polyacrylamide Gel; Fear; Hippocampus; Kindling, Neurologic; Male; Matrix Metalloproteinase 9; Memory; Mice; Mice, Inbred ICR; Mice, Knockout; Microinjections; Nerve Tissue Proteins; Neuroprotective Agents; Pentylenetetrazole; Protein Kinases; Protein Precursors; Receptor, trkB; RNA, Messenger; Seizures

Control of seizure activity is critical to survival and neuroprotection following nerve agent exposure. Extensive research has shown that three classes of drugs, muscarinic antagonists, benzodiazepines, and N-methyl-D: -aspartate antagonists, are capable of moderating these seizures. This study began to map the neural areas in rat brain that respond to these three drug classes resulting in anticonvulsant effects. Drugs of each class (scopolamine, midazolam, MK-801) were evaluated for their ability to prevent sarin-induced seizures when injected into specific brain areas (lateral ventricle, anterior piriform cortex, basolateral amygdala, area tempestas). Animals were pretreated by microinjection with saline or a dose of drug from one of the three classes 30 min prior to receiving 150 microg/kg sarin, subcutaneously, followed by 2.0 mg/kg atropine methylnitrate, intramuscularly. Animals were then returned to their cages, where electroencephalographic activity was monitored for seizures. Anticonvulsant effective doses (ED(50)) were determined using an up-down dosing procedure over successive animals. Scopolamine provided anticonvulsant effects in each area tested, while midazolam was effective in each area except the lateral ventricle. MK-801 was only effective at preventing seizures when injected into the basolateral amygdala or area tempestas. The results show a unique neuroanatomical and pharmacological specificity for control of nerve agent-induced seizures.

Topics: Amygdala; Animals; Anticonvulsants; Brain; Cholinergic Antagonists; Cholinesterase Inhibitors; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroencephalography; Excitatory Amino Acid Antagonists; GABA Modulators; Injections, Intraventricular; Male; Midazolam; Olfactory Pathways; Rats; Rats, Sprague-Dawley; Sarin; Scopolamine; Seizures; Treatment Outcome

Quinolinic acid (QA) is an N-methyl-D-aspartate receptor agonist that also promotes glutamate release and inhibits glutamate uptake by astrocytes. QA is used in experimental models of seizures studying the effects of overstimulation of the glutamatergic system. The guanine-based purines (GBPs), including the nucleoside guanosine, have been shown to modulate the glutamatergic system when administered extracellularly. GBPs were shown to inhibit the binding of glutamate and analogs, to be neuroprotective under excitotoxic conditions, as well as anticonvulsant against seizures induced by glutamatergic agents, including QA-induced seizure. In this work, we studied the electrophysiological effects of guanosine against QA-induced epileptiform activity in rats at the macroscopic cortical level, as inferred by electroencephalogram (EEG) signals recorded at the epidural surface. We found that QA disrupts a prominent basal theta (4-10 Hz) activity during peri-ictal periods and also promotes a relative increase in gamma (20-50 Hz) oscillations. Guanosine, when successfully preventing seizures, counteracted both these spectral changes. MK-801, an NMDA-antagonist used as positive control, was also able counteract the decrease in theta power; however, we observed an increase in the power of gamma oscillations in rats concurrently treated with MK-801 and QA. Given the distinct spectral signatures, these results suggest that guanosine and MK-801 prevent QA-induced seizures by different network mechanisms.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Guanosine; Male; Quinolinic Acid; Rats; Rats, Wistar; Seizures; Spectrum Analysis; Theta Rhythm

In various animals methionine sulfoximine (MSO) induces tonic-clonic seizures resembling the most striking form of human epilepsies. The aim of the present study was to select two lines of mice based upon differences in their latency to MSO-dependent seizures, in order to characterize them.. Random crosses involving eight inbred mice strains were used to generate the starting population in which the first MSO challenge (75 mg/kg, i.p.) was performed. Two groups of 16 breeding pairs were established by mating mice having the shortest (MSO-Fast) and the longest (MSO-Slow) convulsion latencies. Mating and selection by latency to MSO (75 mg/kg, i.p.) was carried out over six generations.. MSO-Fast mice presented a significantly shorter MSO latency, and were more susceptible to MSO than MSO-Slow ones were. Electroencephalography (EEG) alterations were observed during the preconvulsive period when MSO-Fast mice were submitted to 75 mg/kg of MSO, and MSO-Slow ones to 200 mg/kg. Using another convulsant, kainic acid, the latency to convulse of MSO-Fast mice was significantly shorter than that of the MSO-Slow ones, whereas no difference was observed in response to pentylenetetrazole (PTZ). MSO-dependent convulsions were completely antagonized by MK-801, and partially by valproic acid, suggesting a preferential involvement of glutamatergic pathways.. The model that we have developed for MSO "sensitive" and "resistant" mice could allow for a better understanding of MSO mechanisms of epileptogenesis, and it may also constitute a useful approach for therapeutic actions of drugs.

Topics: Animals; Cerebral Cortex; Convulsants; Crosses, Genetic; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electrodes, Implanted; Electroencephalography; Female; Kainic Acid; Male; Methionine Sulfoximine; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Pentylenetetrazole; Reaction Time; Seizures; Selection, Genetic

We previously have identified phenotypic differences in susceptibility to hippocampal seizure-induced cell death among two inbred strains of mice. We have also reported that the age-related increased susceptibility to the neurotoxic effects of seizure-induced injury is regulated in a strain-dependent manner. In the present study, we wanted to begin to determine the pharmacological mechanism that contributes to variability in the response to the neurotoxic effects of kainate. Thus, we compared the effects of the NMDA receptor antagonist, MK-801 and of the AMPA receptor antagonist NBQX on hippocampal damage in the kainate model of seizure-induced excitotoxic cell death in young, middle-aged, and aged C57BL/6 and FVB/N mice, when given 90 min following kainate-induced status epilepticus. Following kainate injections, mice were scored for seizure activity and brains from mice in each age and antagonist group were processed for light microscopic histopathologic evaluation 7 days following kainate administration to evaluate the severity of seizure-induced injury. Administration of MK-801 significantly reduced the extent of hippocampal damage in young, mature and aged FVB/N mice, while application of NBQX was only effective at attenuating cell death in young and aged mice throughout all hippocampal subfields. Our results suggest that both NMDA and non-NMDA receptors are involved in kainate-induced cell death in the mouse and suggest that aging may differentially affect the ability of neuroprotectants to protect against hippocampal damage. Differences in the effectiveness of these two antagonists could result from differential regulation of glutamatergic neurotransmitter systems or ion channel specificity.

Topics: Age Factors; Analysis of Variance; Animals; Brain; Cell Count; Cell Death; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Fluorescent Antibody Technique; Kainic Acid; Mice; Neurons; Neuroprotective Agents; Quinoxalines; Seizures; Severity of Illness Index; Species Specificity

Importins, also called karyopherins, belong to a large family of proteins involved in cytoplasm-to-nucleus transport. Transport machinery generally involves a complex formed by two different importin subtypes (alpha and beta). Both alpha and beta importins are expressed in the brain, and their expression and localization is regulated by physiological neuronal activity. Little is known about regulation of importin expression in brain pathological conditions. Here we studied the expression of importin beta1 (imp beta 1) in the rat hippocampus after acute and chronic seizures induced by the glutamate agonist kainic acid (KA). The overall content of imp beta 1 mRNA and protein did not change after acute KA seizures. However, acute KA seizures rapidly induced the translocation of imp beta 1 protein from the cytoplasm to the nucleus in pyramidal CA1 neurons. KA-induced imp beta 1 translocation was prevented by the NMDA (N-methyl-D-aspartic acid) receptor blocker MK-801. After chronic seizures, the overall levels of imp beta 1 mRNA and protein did not change in the whole hippocampus. Immunohistochemistry revealed a massive loss of imp beta 1-positive neurons in pyramidal layers (that degenerated after KA), whereas an increased number of imp beta 1-positive cells was detected in the stratum radiatum of rats with chronic seizures compared with control animals. Double-labeling experiments identified these cells as glial cells expressing the chondroitin sulfate proteoglycan NG2 (neuron/glial antigen 2), a glial subtype recently shown to regulate hippocampal neuron excitability. These data show a differential regulation of imp beta 1 expression after acute and chronic seizure activity in the rat hippocampus.

Topics: Animals; Antigens; beta Karyopherins; Cell Death; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Gene Expression; Hippocampus; Kainic Acid; Male; Neuroglia; Proteoglycans; Pyramidal Cells; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures

The major aim of this study was to elucidate the relationship between nitric oxide (NO) and generalized epilepsy. Mice lacking the neuronal nitric oxide synthase (nNOS) gene (nNOS(-/-)) were used in this study to determine the relationship between nNOS alpha and NO in pentylentetrazole (PTZ)-induced convulsions. nNOS(-/-) mice exhibited severe convulsions following injection with a subconvulsive dose of PTZ (40 mg/kg i.p.) and convulsive doses were lethal in all of the mice (60 mg/kg i.p.) following tonic convulsions. The results were confirmed by using selective nNOS inhibitors in wild-type (nNOS(+/+)) mice. The higher doses of the nNOS inhibitors 1-[2-(trifluoromethyl)phenyl] imidazole (TRIM) and 3-bromo-7-nitroindazole (3Br7NI) inhibited clonic-tonic convulsions induced by a convulsive dose of PTZ (60 mg/kg) in nNOS(+/+) mice. In contrast, either TRIM or 3Br7NI at lower doses enhanced convulsions following injection with a subconvulsive dose of PTZ (40 mg/kg) in nNOS(+/+) mice similar to nNOS(-/-) mice treated with PTZ. Such a proconvulsant effect was observed in nNOS(+/+) mice pretreated with nNOS inhibitors but not other NOS inhibitors. These results indicate that NO may be regarded as an anticonvulsant or a proconvulsant substance in relation to convulsions induced by PTZ in mice. Pretreatment with N-methyl-d-aspartate (NMDA) receptor antagonists (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine maleate (MK-801), (E)-(+/-)-2-amino-4-methyl-5-phospho no-3-pentenoic acid ethyl ester, CGP39551) and DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide, NBQX) inhibited a subconvulsive dose of PTZ-induced convulsions in nNOS(-/-) mice, demonstrating that convulsions induced by PTZ are modulated by endogenous NO production and ionotropic glutamate receptor-mediated stimulation. These results suggest a negative or positive modulation of neuronal interactions by basal or enhanced NO production, respectively.

Topics: Animals; Convulsants; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Gene Expression Regulation; Imidazoles; Indazoles; Mice; Mice, Inbred C57BL; Mice, Knockout; N-Methylaspartate; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase Type I; Pentylenetetrazole; Quinoxalines; Seizures

The mechanism of anticonvulsant action of topiramate includes inhibition of glutamate-activated ion channels. The evidence is most convincing for direct inhibitory action at the ionotropic AMPA (alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and kainate ((2S,3S,4S)-3-(Carboxymethyl)-4-prop-1-en-2-ylpyrrolidine-2-carboxylic acid) glutamate receptor subtypes. Less direct connection has been made to the NMDA (N-Methyl-d-aspartate) subtype. In the present study, we demonstrate that NMDA and AMPA produce concentration-dependent seizure-like activity in planarians, a type of flatworm which possesses mammalian-like neurotransmitters. In contrast, planarians exposed to the inhibitory amino acid, glycine, did not display pSLA. For combination experiments, topiramate significantly reduced planarian seizure-like activity (pSLA) produced by NMDA or AMPA. Additionally, NMDA-induced pSLA was antagonized by either an NMDA receptor antagonist (MK-801) or AMPA receptor antagonist (DNQX), thus suggesting that NMDA-induced pSLA was mediated by NMDA and non-NMDA receptors. The present results provide pharmacologic evidence of a functional inhibitory action of topiramate on glutamate receptor activity in invertebrates and provide a sensitive, quantifiable end-point for studying anti-seizure pharmacology.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Behavior, Animal; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Fructose; N-Methylaspartate; Neuroprotective Agents; Planarians; Quinoxalines; Seizures; Topiramate

This study investigated the anticonvulsant effect of 3-alkynyl selenophene (3-ASP) on pilocarpine (PC)-, pentylenetetrazole (PTZ)- and kainic acid (KA)-induced seizures and mortality in 21-day-old rats. Rats were pretreated by oral route (p.o.) with 3-ASP (10, 25 and 50mg/kg) before intraperitoneal (i.p.) administration of PC (400mg/kg), PTZ (80 mg/kg) or KA (45 mg/kg). 3-ASP increased the latency to the seizure onset on PTZ and KA models. At the dose of 50mg/kg, 3-ASP avoided the death caused by PTZ and KA. 3-ASP (50mg/kg) abolished seizures and death induced by PC in rats. To investigate the antioxidant effect of 3-ASP on rats exposed to PC, the activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), acetylcholinesterase (AChE), Na(+)K(+)ATPase, superoxide dismutase (SOD) and catalase (CAT) as well as the levels of reactive species (RS) and ascorbic acid (AA) were determined in brains of rats. 3-ASP protected against the increase in RS levels and CAT activity induced by PC in brains of rats. The decrease in the levels of AA and inhibition of Na(+)K(+)ATPase, SOD and AChE activities caused by PC were protected by 3-ASP. Subeffective doses of 3-ASP plus diazepam, 5S,10R-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) or 6,7-dinitroquinoxaline-2,3-dione (DNQX) increased the latency to the seizure onset induced by PC, suggesting the involvement of ionotropic glutamatergic and GABAergic receptors in anticonvulsant action of 3-ASP. The anticonvulsant and antioxidant effects of 3-ASP in 21-day-old rats on PC model were demonstrated.

Topics: Animals; Anticonvulsants; Antioxidants; Brain; Diazepam; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Kainic Acid; Male; Organoselenium Compounds; Pentylenetetrazole; Pilocarpine; Quinoxalines; Rats; Rats, Wistar; Seizures; Time Factors; Treatment Outcome

Early-life stress has been shown to destabilize the homeostatic synaptic plasticity and compromise the developing brain to the later encountered insults. This study would determine the long-term epileptogenic effect of neonatal isolation (NI) on early-life seizure. There were five groups: normal rearing (NR) rats; NI rats; NR rats suffering from status epilepticus (SE) at P12 (NR-SE); NI-SE rats; NI-SE-MK801 rats. All adult rats were video monitored to detect behavioral seizures, examined with brain magnetic resonance imaging, and assessed for hippocampal NeuN-immunoreactive (NeuN-IR) cells. Behavioral seizures were detected in one of six NR-SE rats, all the NI-SE rats (eight of eight), and none in the NR, NI, or NI-SE-MK801 rats. High hippocampal T2 signal were only found in three of five NR-SE rats, five of six NI-SE rats, and one of five NI-SE-MK801 rats. There was a significant decrease in the number of hippocampal NeuN-IR cells in the NR-SE and NI-SE groups, compared with the NR group, and MK-801 treatment ameliorated the neuronal loss. Our results demonstrated that NI led to an increase in epileptogenesis in rat pups with early-life SE, and treatment with MK-801 could ameliorate brain injuries, indicating a critical role of N-methyl-d-aspartic acid receptor in the epileptogenic process.

Topics: Animals; Animals, Newborn; Behavior, Animal; Dizocilpine Maleate; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Pregnancy; Rats; Rats, Sprague-Dawley; Seizures; Social Isolation; Status Epilepticus

Human immunodeficiency virus-1 (HIV-1) infection may produce neurological deficits, such as cognitive decline, that may be worsened by concurrent ethanol (EtOH) abuse. Among the many biochemical cascades likely mediating HIV-1-associated neuronal injury is enhancement of N-methyl-d-aspartate (NMDA) receptor function and progression to excitotoxicity, an effect that may be directly or indirectly related to accumulation in brain of the HIV-1 trans-activator of transcription (Tat) factor. The present studies were designed to examine the hypothesis that binge-like EtOH pre-exposure would enhance effects of Tat on NMDA receptor function. These studies employed a modified in vivo binge EtOH exposure regimen designed to produce peak blood EtOH levels (BEL) of <200 mg/dl in adult male rats and were designed to examine effects of intra-hippocampal injection of Tat (0.5 microl/500 pM/2 min) on EtOH withdrawal-related behavior, spatial learning, and histological measures. Unilateral cannulae were implanted into the cornu ammonis 1 (CA1) pyramidal cell layer of animals prior to beginning a 4-day binge EtOH regimen. EtOH was administered via intragastric intubation ( approximately 3.0-5.0 g/kg) with dose determined by behavioral ratings of intoxication daily for 4 days (at 08:00, 16:00, and 24:00 h). EtOH withdrawal behaviors were monitored 12 h after the last administration of EtOH. Morris water maze learning was assessed during the following 4 days, at which times brains were harvested for autoradiographic measurement of NMDA receptor density and neuroinflammation. Maximal BELs of 187.69 mg/dl were observed 60 min after EtOH administration on day 2 of the regimen. In contrast, peak BELs of approximately 100 mg/dl were observed 60 min after EtOH administration on day 4 of the regimen, suggesting development of metabolic tolerance. Significant behavioral abnormalities were observed in EtOH withdrawn animals, including tremor and seizures. Intra-CA1 region injection of Tat significantly potentiated EtOH withdrawal behavioral abnormalities, an effect that was reduced by MK-801 pre-exposure. While EtOH withdrawn animals showed learning similar to control animals, EtOH withdrawn animals that received intra-CA1 Tat injection demonstrated persisting deficits in spatial learning on days 3 and 4 of training, effects that were markedly reduced by administration of the competitive NMDA receptor antagonist MK-801 30 min prior to Tat injection. No changes in [(3)H]MK-801 binding

Topics: Animals; Autoradiography; Dizocilpine Maleate; Ethanol; Hippocampus; Injections, Intraventricular; Isoquinolines; Male; Maze Learning; Microglia; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Seizures; Spatial Behavior; Substance Withdrawal Syndrome; tat Gene Products, Human Immunodeficiency Virus

Theophylline-associated convulsions have been observed most frequently in children with fever, but the mechanism is not fully understood. In this study, we investigated the basic mechanism of aminophylline [theophylline-2-ethylenediamine]-induced convulsions and the effects of Brewer's yeast-induced pyrexia in mice. Diazepam (5-10mg/kg, i.p.), a benzodiazepine receptor agonist, significantly prolonged the onset and significantly decreased the incidence of convulsions induced by aminophylline (350 mg/kg, i.p.). However, the gamma aminobutyric acid (GABA)A receptor agonist muscimol (1-4 mg/kg, i.p.), the GABAB receptor agonist baclofen (2-4 mg/kg, i.p.) and the N-methyl-D-aspartic acid receptor antagonist dizocilpine (0.1-0.3 mg/kg, i.p.) failed to protect against the convulsions. 20% Brewer's yeast (0.02 ml/g, s.c.) increased body temperature by 1.03, and also significantly shortened the onset and significantly increased the incidence of convulsions induced by aminophylline. The anticonvulsant action of diazepam (2.5-10mg/kg, i.p.) on the convulsions induced by aminophylline was reduced by Brewer's yeast-induced pyrexia. The proconvulsant actions of the GABAA receptor antagonists picrotoxin (3-4 mg/kg, i.p.) and pentylenetetrazol (40-60 mg/kg, i.p.) were enhanced by Brewer's yeast. These results suggest that the anticonvulsant action of diazepam against aminophylline is reduced by Brewer's yeast-induced pyrexia, and that GABAA receptors are involved in the aggravation of the convulsions by Brewer's yeast in mice.

Topics: Aminophylline; Animals; Anticonvulsants; Apnea; Bronchodilator Agents; Child; Convulsants; Diazepam; Dizocilpine Maleate; Fever; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; GABA-B Receptor Agonists; Humans; Infant; Japan; Male; Mice; Neuroprotective Agents; Pentylenetetrazole; Picrotoxin; Purinergic P1 Receptor Agonists; Saccharomyces cerevisiae; Seizures

Abnormal glutamatergic activity is implicated in neurologic and neuropsychiatric disorders. Selective glutamate receptor antagonists were highly effective in animal models of stroke and seizures but failed in further clinical development because of serious side effects, including an almost complete set of symptoms of schizophrenia. Therefore, the novel polyvalent glutamatergic agent 3,5-dibromo-L-phenylalanine (3,5-DBr-L-Phe) was studied in rat models of stroke, seizures and sensorimotor gating deficit.. 3,5-DBr-L-Phe was administered intraperitoneally as three boluses after intracerebral injection of endothelin-1 (ET-1) adjacent to the middle cerebral artery to cause brain injury (a model of stroke). 3,5-DBr-L-Phe was also given as a single bolus prior to pentylenetetrazole (PTZ) injection to induce seizures or prior to the administration of the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) to cause disruption of prepulse inhibition (PPI) of startle (sensorimotor gating deficit).. Brain damage caused by ET-1 was reduced by 52%, which is comparable with the effects of MK-801 in this model as reported by others. 3,5-DBr-L-Phe significantly reduced seizures induced by PTZ without the significant effects on arterial blood pressure and heart rate normally caused by NMDA antagonists. 3,5-DBr-L-Phe prevented the disruption of PPI measured 3 days after the administration of ET-1. 3,5-DBr-L-Phe also eliminated sensorimotor gating deficit caused by MK-801.. The pharmacological profile of 3,5-DBr-L-Phe might be beneficial not only for developing a therapy for the neurological and cognitive symptoms of stroke and seizures but also for some neuropsychiatric disorders.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Endothelin-1; Gait Disorders, Neurologic; Glutamic Acid; Male; Pentylenetetrazole; Phenylalanine; Rats; Rats, Sprague-Dawley; Reflex, Startle; Seizures; Stroke

Stress is a part of our daily life, inducing neurochemical and neurophysiological changes in the central nervous system.. The present study was designed to investigate the importance of sex differences in the interaction between dizocilpine (MK-801) pretreatment and acute cold-restraint stress (CRS) in pentylenetetrazole (PTZ)-induced seizures in Swiss albino mice.. A CRS protocol was applied to mice to investigate the interaction between MK-801 pretreatment (30 min before CRS) and stress (followed by PTZ injection) in epilepsy susceptibility. For this purpose, 6 groups were designated: (1) PTZ control group (received only PTZ); (2) stress group (received stress and PTZ); (3) saline group (received saline and PTZ); (4) MK-801 group (received MK-801 and PTZ); (5) saline + stress group (received saline, stress, and PTZ); and (6) MK-801 + stress group (received MK-801, stress, and PTZ).. Pretreatment with MK-801 (0.125, 0.25, 0.50 mg/kg) significantly potentiated the protective effect of stress in PTZ-induced (65 mg/kg) seizures in both sexes by prolonging the onset of myoclonic jerks and clonic convulsions. Male mice had a significantly greater delay in the onset of myoclonic jerks (males, 66.7-295.5 sec; females, 54.0-247.5 sec; P < 0.05) and clonic convulsions (males, 123.5-789.8 sec; females, 94.5-757.2 sec; P < 0.05) compared with female mice in all groups (ie, PTZ control, stress, saline, MK-801, saline + stress, and MK-801 + stress groups).. The findings of this study in mice suggest the involvement of sex hormones in the interaction between MK-801 pretreatment and acute CRS in PTZ-induced seizures.

Topics: Animals; Cold Temperature; Dizocilpine Maleate; Epilepsies, Myoclonic; Female; Male; Mice; Mice, Inbred Strains; Models, Animal; Neuroprotective Agents; Pentylenetetrazole; Restraint, Physical; Seizures; Sex Factors; Stress, Psychological

Delayed-rectifier Kv2.1 potassium channels regulate somatodendritic excitability during periods of repetitive, high-frequency activity. Recent evidence suggests that Kv2.1 channel modulation is linked to glutamatergic neurotransmission. Because NMDA-type glutamate receptors are critical regulators of synaptic plasticity, we investigated NMDA receptor modulation of Kv2.1 channels in rodent hippocampus and cortex. Bath application of NMDA potently unclustered and dephosphorylated Kv2.1 and produced a hyperpolarizing shift in voltage-dependent activation of voltage-sensitive potassium currents (I(K)). In contrast, driving synaptic activity in Mg2+-free media to hyperactivate synaptic NMDA receptors had no effect on Kv2.1 channels, and moderate pentylenetetrazole-induced seizure activity in adult mice did not dephosphorylate hippocampal Kv2.1 channels. Selective activation of extrasynaptic NMDA receptors unclustered and dephosphorylated Kv2.1 channels and produced a hyperpolarizing shift in neuronal I(K). In addition, inhibition of glutamate uptake rapidly activated NMDA receptors and dephosphorylated Kv2.1 channels. These observations demonstrate that regulation of intrinsic neuronal activity by Kv2.1 is coupled to extrasynaptic but not synaptic NMDA receptors. These data support a novel mechanism for glutamate transporters in regulation of neuronal excitability and plasticity through extrasynaptic NMDA receptor modulation of Kv2.1 channels.

Topics: Amino Acid Transport System X-AG; Analysis of Variance; Animals; Animals, Newborn; Cells, Cultured; Cerebral Cortex; Disks Large Homolog 4 Protein; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Hippocampus; Intracellular Signaling Peptides and Proteins; Male; Membrane Potentials; Membrane Proteins; N-Methylaspartate; Neurons; Organ Culture Techniques; Patch-Clamp Techniques; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Shab Potassium Channels; Synapses

Guanosine, a purine nucleotide, promotes the reuptake of l-glutamate by astrocytes; astrocytic reuptake of glutamate is a major mechanism of its synaptic inactivation. The current experiments showed that guanosine reduced the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor "open-channel" blocker, to raise the threshold voltage for electrically-precipitated tonic hindlimb extension in unstressed intact mice. This modulatory effect may be due to guanosine's removal of glutamate from the synaptic cleft, resulting in a reduced proportion of NMDA receptor-associated ion channels in the open configuration. The modulatory effect of guanosine on MK-801's ability to disrupt rotorod performance in unstressed mice or antagonize electrically-precipitated seizures in stressed mice was not seen. The inability to demonstrate modulation in the rotorod paradigm may reflect the sensitivity of this measure of motor incoordination to MK-801's disruptive effects. Whereas failure to see this effect in our incremental electroconvulsive shock paradigm in stressed mice may be due to the fact that stress and guanosine act in the same direction to reduce MK-801's antiseizure efficacy. Given the phencyclidine model of schizophrenia and its pharmacological actions as a noncompetitive NMDA receptor "open-channel" blocker and guanosine's antagonistic effect on MK-801's antiseizure efficacy in unstressed mice, the current data support development of guanine-based purines for the treatment of at least some aspects of schizophrenia.

Topics: Animals; Behavior, Animal; Cold Temperature; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroshock; Excitatory Amino Acid Antagonists; Guanosine; Male; Mice; Postural Balance; Receptors, N-Methyl-D-Aspartate; Seizures; Stress, Psychological; Swimming; Synaptic Transmission

Ceramide is known to induce programmed cell death (PCD) in neural and non-neural tissues and to increase after kainic acid (KA) status epilepticus (SE). Ceramide increases have been shown to depend on NMDA receptor activation in the KA model, but these changes have not been studied in the lithium pilocarpine (LiPC) model. Thus, the purpose of this study was to determine if hippocampal ceramide levels increase after LiPC induced SE and if NMDA receptor blockade prevents PCD and any such ceramide increases. We found that LiPC induced SE resulted in ceramide increases and DNA fragmentation in the hippocampus of adult, P21, and P7 rats. The administration of MK-801, the NMDA receptor antagonist, in adults, 15min prior to pilocarpine, prevented ceramide increases, and DNA fragmentation.

Topics: Animals; Cell Death; Ceramides; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Humans; In Situ Nick-End Labeling; Kainic Acid; Lithium; Male; Pilocarpine; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

About 30% of patients with epilepsy do not respond adequately to drug therapy, making pharmacoresistance a major problem in the treatment of this common brain disorder. Mechanisms of intractability are not well understood, but may include limitation of antiepileptic drug access to the seizure focus by overexpression of the drug efflux transporter P-glycoprotein (Pgp) at the blood-brain barrier. Increased expression of Pgp has been determined both in epileptogenic brain tissue of patients with intractable epilepsy and in rodent models of temporal lobe epilepsy, including the pilocarpine model. The mechanisms underlying the increase of Pgp after seizures are unclear. We have recently suggested that the excitatory neurotransmitter glutamate, which is excessively released by seizures, is involved in the seizure-induced overexpression of Pgp in the brain. This hypothesis was evaluated in the present study in the pilocarpine model in rats. After 90 min of status epilepticus (SE), diazepam was administered, followed by either vehicle or the glutamate receptor antagonist MK-801 (dizocilpine). Following SE in vehicle treated rats, Pgp expression in brain capillary endothelial cells increased about twofold in the hippocampus, which was completely prevented by MK-801. Furthermore, neurodegeneration developing in the hippocampus and parahippocampal regions was reduced by the glutamate antagonist. In contrast, the Pgp inhibitor tariquidar did not affect the SE-induced overexpression of Pgp or neurodegeneration in most regions examined. The data indicate that seizure-induced glutamate release is involved in the regulation of Pgp expression, which can be blocked by MK-801. The finding that MK-801 counteracts both Pgp overexpression and neuronal damage when administered after SE may offer a clinically useful therapeutic option in patients with refractory SE.

Topics: Animals; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Brain Chemistry; Capillaries; Dizocilpine Maleate; Epilepsy, Temporal Lobe; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Image Processing, Computer-Assisted; Immunohistochemistry; Muscarinic Agonists; Nerve Degeneration; Pilocarpine; Quinolines; Rats; Rats, Wistar; Seizures; Status Epilepticus

Glycine encephalopathy (GE) is caused by an inherited deficiency of the glycine cleavage system (GCS) and characterized by accumulation of glycine in body fluids and various neurologic symptoms. Coma and convulsions develop in neonates in typical GE while psychomotor retardation and behavioral abnormalities in infancy and childhood are observed in mild GE. Recently, we have established a transgenic mouse line (low-GCS) with reduced GCS activity (29% of wild-type (WT) C57BL/6) and accumulation of glycine in the brain (Stroke, 2007; 38:2157). The purpose of the present study is to characterize behavioral features of the low-GCS mouse as a model of mild GE. Two other transgenic mouse lines were also analyzed: high-GCS mice with elevated GCS activity and low-GCS-2 mice with reduced GCS activity. As compared with controls, low-GCS mice manifested increased seizure susceptibility, aggressiveness and anxiety-like activity, which resembled abnormal behaviors reported in mild GE, whereas high-GCS mice were less sensitive to seizures, hypoactive and less anxious. Antagonists for the glycine-binding site of the N-methyl-D-aspartate receptor significantly ameliorated elevated locomotor activity and seizure susceptibility in the low-GCS mice. Our results suggest the usefulness of low-GCS mice as a mouse model for mild GE and a novel therapeutic strategy.

Topics: Aggression; Amino Acid Oxidoreductases; Animals; Anxiety; Binding Sites; Brain Diseases, Metabolic; Carrier Proteins; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glycine; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Multienzyme Complexes; Pyrrolidinones; Quinolones; Receptors, N-Methyl-D-Aspartate; Seizures; Transferases

Alpha2-adrenoreceptor (alpha(2)-AR) antagonists have been shown to improve, while alpha(2)-AR agonists impair cognitive function in subjects with functioning NMDA receptors (NMDAR). In subjects with inhibited NMDAR (a model of schizophrenia) alpha(2)-AR agonists attenuate the cognitive impairments. The effect with alpha(2)-AR antagonists remains unclear.. We investigated the effects of the alpha(2)-AR antagonist idazoxan on memory function in rats treated/not treated with NMDAR antagonist dizocilpine or a combination of dizocilpine and nicotine to clarify noradrenergic/cholinergic regulation of memory function.. Female Sprague-Dawley rats (n=12) were trained for food reward on the radial maze. Working and reference memory errors and response latency were assessed after injections of idazoxan (0.5, 1.0 mg/kg), dizocilpine (0.05 mg/kg), nicotine (0.2, 0.4 mg/kg) or vehicle, alone or in combination.. Dizocilpine potently impaired memory. Nicotine (0.4 mg/kg) reversed this impairment. Idazoxan at the doses tested did not affect performance when given alone or with dizocilpine, but it did block the nicotine reversal of the dizocilpine-induced memory impairment. Three rats after 10-12 drug treatments developed limbic seizures. Our findings suggest that combination of drugs which block alpha(2)-AR with nicotinic agonists in schizophrenia may prevent therapeutic effect of nicotinic agonists and increase risk for convulsive activity with repeated administration.

Topics: Adrenergic alpha-Antagonists; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Idazoxan; Maze Learning; Memory; Memory Disorders; Memory, Short-Term; Nicotine; Nicotinic Agonists; Norepinephrine; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Synaptic Transmission

NMDA receptor hypofunction (NRH) has been implicated in the pathophysiology of schizophrenia because of the ability of phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, to precipitate a schizophreniform psychosis. The possible role that NRH plays in the pathophysiology of schizophrenia stimulated characterization of behaviors elicited by PCP and its analogues. For example, MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist that binds with higher affinity to the same hydrophobic channel domain as PCP, raises the threshold voltage required for the electrical precipitation of tonic hindlimb extension in mice. This ability of MK-801 is significantly reduced following stress. We showed that an exogenously administered glycine prodrug (i.e., milacemide) was able to potentiate MK-801's antiseizure efficacy in unstressed mice and restore MK-801's antiseizure efficacy in stressed animals. d-Serine may serve as an endogenous agonist for the obligatory glycine co-agonist site on the NMDA receptor complex. Orally administered d-serine has been studied clinically as an adjuvant therapeutic intervention in schizophrenia. Thus, we were surprised at its inability to potentiate MK-801's antiseizure efficacy in either control or stressed animals. These data do not support the development of d-serine as a viable therapeutic intervention for schizophrenia and, possibly, other disorders.

Topics: Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Interactions; Electroshock; Male; Mice; Neuroprotective Agents; Seizures; Serine

Organophosphate (OP) and carbamate acetylcholinesterase (AChE) inhibitors produce seizures and lethality in mammals. Anticonvulsant and neuroprotective properties of N-methyl-D-aspartate (NMDA) antagonists encourage the investigation of their effects in AChE inhibitor-induced poisonings. In the present study, the effects of dizocilpine (MK-801, 1 mg/kg) or 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 10 mg/kg), alone or combined with muscarinic antagonist atropine (1.8 mg/kg), on convulsant and lethal properties of an OP pesticide dichlorvos or a carbamate drug physostigmine, were studied in mice. Both dichlorvos and physostigmine induced dose-dependent seizure activity and lethality. Atropine did not prevent the occurrence of convulsions but decreased the lethal effects of both dichlorvos and physostigmine. MK-801 or CPP blocked or attenuated, respectively, dichlorvos-induced convulsions. Contrariwise, NMDA antagonists had no effect in physostigmine-induced seizures or lethality produced by dichlorvos or physostigmine. Concurrent pretreatment with atropine and either MK-801 or CPP blocked or alleviated seizures produced by dichlorvos, but not by physostigmine. Both MK-801 and CPP co-administered with atropine enhanced its antilethal effects in both dichlorvos and physostigmine poisoning. In both saline- and AChE inhibitor-treated mice, no interaction of the investigated antidotes with brain cholinesterase was found. The data indicate that both muscarinic ACh and NMDA receptor-mediated mechanisms contribute to the acute toxicity of AChE inhibitors, and NMDA receptors seem critical to OP-induced seizures.

Topics: Animals; Atropine; Carbamates; Cholinesterase Inhibitors; Dichlorvos; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Therapy, Combination; Lethal Dose 50; Male; Mice; N-Methylaspartate; Piperazines; Seizures

Methylmalonic acid (MMA) is an endogenous convulsing compound that accumulates in methylmalonic acidemia, an inborn error of the metabolism characterized by severe neurological dysfunction, including seizures. The mechanisms by which MMA causes seizures involves the activation of the N-methyl-D-aspartate (NMDA) receptors, but whether GABAergic mechanisms are involved in the convulsions induced by MMA is not known. Therefore, in the current study we investigated the involvement of GABAergic mechanisms in the convulsions induced by MMA. Adult rats were injected (i.c.v.) with muscimol (46 pmol/1 microl), baclofen (0.03, 0.1 and 0.3 micromol/1 microl), MK-801 (6 nmol/1 microl), pyridoxine (2 micromol/4 microl) or physiological saline (0.15 micromol/1 microl). After 30 min, MMA (0.3, 0.1 and 3 micromol/1 microl) or NaCl (6 micromol/1 microl, i.c.v.) was injected. The animals were immediately transferred to an open field and observed for the appearance of convulsions. After behavioral evaluation, glutamic acid decarboxylase (GAD) activity was determined in cerebral cortex homogenates by measuring the 14CO2 released from l-[14C]-glutamic acid. Convulsions were confirmed by electroencephalographic recording in a subset of animals. MMA caused the appearance of clonic convulsions in a dose-dependent manner and decreased GAD activity in the cerebral cortex ex vivo. GAD activity negatively correlated with duration of MMA-induced convulsions (r=-0.873, P<0.01), in an individual basis. Muscimol, baclofen, MK-801 and pyridoxine prevented MMA-induced convulsions, but only MK-801 and pyridoxine prevented MMA-induced GAD inhibition. These data suggest GABAergic mechanisms are involved in the convulsive action of MMA, and that GAD inhibition by MMA depends on the activation of NMDA receptors. While in this study we present novel data about the role of the GABAergic system in MMA-induced convulsions, the central role of NMDA receptors in the neurochemical actions of MMA is further reinforced since they seem to trigger GABAergic failure.

Topics: Analysis of Variance; Animals; Baclofen; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Electroencephalography; Excitatory Amino Acid Antagonists; GABA Agonists; gamma-Aminobutyric Acid; Gene Expression Regulation, Enzymologic; Glutamate Decarboxylase; Male; Methylmalonic Acid; Muscimol; Rats; Rats, Wistar; Seizures

Potentiation of GABA(A) receptor-mediated inhibitory neurotransmission contributes to the anesthetic action of thiopental. However, the inhibiting action of general anesthetic on excitatory neurotransmission also purportedly underlies its effects. The aim of the study was to elucidate the role of glutamate receptors (NMDA and AMPA receptors) in thiopental-induced anesthesia. Intracerebroventricular (i.c.v.) NMDA (50 ng) significantly increased the induction time of loss of righting reflex and decreased sleep time induced by intraperitoneal injection (i.p.) of thiopental (50 mg/kg). Furthermore, NMDA at 50 ng i.c.v. increased the 50% effective dose values for thiopental to produce loss of righting reflex and immobility in response to noxious tail clamp by 25% and 21% (p < 0.05), respectively. However, intrathecal (IT) administration of NMDA or both of i.c.v. or IT administration of AMPA did not show such antagonizing effects on thiopental action at subconvulsive dose. Finally, thiopental (25 mg/kg i.p.) inhibited convulsions induced by NMDA (0.4 microg i.c.v.) or bicuculline (0.6 microg i.c.v.). However, i.p. muscimol (1 mg/kg) blocked the convulsions induced by bicuculline, but not those induced by NMDA at 3 mg/kg. Similarly, i.p. MK-801 (0.1 mg/kg) antagonized NMDA-induced convulsions, but not bicuculline-induced convulsions at 0.3 mg/kg. Therefore, we suggest that the effects of the selective GABA(A) and NMDA receptors on convulsive behavior are special to their sites of action, and that the inhibitory action of thiopental on NMDA receptors is possibly not mediated by secondary effects of its GABA(A) receptors agonism. These results above indicate the involvement of NMDA receptors in thiopental-induced anesthesia in mice.

Topics: Analgesics; Anesthetics, Intravenous; Animals; Anticonvulsants; Behavior, Animal; Bicuculline; Dizocilpine Maleate; Female; GABA Agonists; GABA Antagonists; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; Male; Mice; Movement; Muscimol; N-Methylaspartate; Pain Measurement; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Reflex, Abnormal; Seizures; Thiopental

Reactive glial cells, for example, from patients with temporal lope epilepsy have a reduced density of inward rectifying K(+) (Kir) channels and thus a reduced K(+) buffering capacity. Evidence is accumulating that this downregulation of Kir channels could be implicated in epileptogenesis. In rat hippocampal brain slices, prolonged exposure to the nonselective Kir channel antagonist, Cs(+) (5 mM), gives rise to an epileptiform field potential (Cs-FP) in area CA1 composed of an initial positive (interictal-like) phase followed by a prolonged negative (ictal-like) phase. We have previously shown that the interictal-like phase depends on synaptic activation. The present study extends these findings by showing that the ictal-like phase of the Cs-FP is (i) sensitive to osmotic expansion of the extracellular space, (ii) reversed very quickly during wash out of Cs(+), and (iii) re-established in the presence of Ba(2+) (30-200 microM) or isosmotic low extracellular concentration of Na(+) ([Na(+)](o), 51.25 mM). The interictal-like phase showed less or no sensitivity to these treatments. In the complete absence of Cs(+), the Cs-FP could be fully reconstructed by the combined application of 4-aminopyridine (0.5 mM), an isosmotic high extracellular concentration of K(+) ([K(+)](o), 7 mM), and low [Na(+)](o) (51.25 mM). These results suggest that the interictal-like phase is initiated through synaptic activation and results from an unspecific increase in neuronal excitability, whereas the ictal-like phase is entirely dependent on blockade of Kir channels in CA1. We propose that glial dysfunction-related loss of Kir channels may not alone be sufficient for starting the induction process, but will likely increase the tendency of an epileptogenic process to proceed into seizure activity.

Topics: 4-Aminopyridine; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Barium; Cesium; Dizocilpine Maleate; Electric Stimulation; Excitatory Amino Acid Antagonists; Hippocampus; In Vitro Techniques; Male; Membrane Potentials; Neuroglia; Patch-Clamp Techniques; Potassium Channel Blockers; Potassium Channels, Inwardly Rectifying; Rats; Rats, Wistar; Seizures; Synaptic Transmission

Seizure incidence during the neonatal period is higher than any other period in the lifespan, yet we know little about this period in terms of the effect of seizures or of the drugs used in their treatment. The fact that several antiepileptic drugs (AEDs) induce pronounced apoptotic neuronal death in specific regions of the immature brain prompts a search for AEDs that may be devoid of this action. Furthermore, there is a clear need to find out if a history of seizures alters the proapoptotic action of the AEDs. Our studies are aimed at both of these issues. Phenytoin, valproate, phenobarbital, and MK801 each induced substantial regionally specific cell death, whereas levetiracetam even in high doses (up to 1,500 mg/kg) did not have this action. In view of our previously findings of neuroprotective actions of repeated seizures in the adult brain, we also examined repeated seizures for a possible antiapoptotic action in the infant rat. Rat pups were preexposed to electroshock seizures (ECS) for 3 days (age 5-7 days) before receiving MK801 on day 7. The effect of ECS, which was consistently a 30% decrease in MK801-induced programmed cell death (PCD), suggests that repeated seizures can exert an antiapoptotic action in the infant brain. In contrast, PCD induced by valproate was not attenuated by ECS preexposure, suggesting that valproate-induced PCD is mechanistically distinct from that induced by MK801 and may not be activity-dependent. Presently, we do not know if this neuroprotective effect of seizures is deleterious or beneficial. If the seizures also enhance the survival of neurons that are destined to undergo naturally occurring PCD, early childhood seizures may have deleterious effects by preventing this necessary component of normal development. While this effect of seizures might be counteracted by AEDs, the fact that several AEDs shift the PCD to the other extreme, and trigger excessive neuronal cell loss, raises concern about whether the drug therapy may be more detrimental than the seizures. In this context, it is encouraging that we have identified at least one AED that is devoid of a proapoptotic action in the infant brain, even in high doses. It is now important to evaluate the long-term consequences of the changes in PCD in infancy by examining behavioral outcomes and seizure susceptibility in the AED- and seizure-exposed neonates when they reach adulthood.

Topics: Animals; Animals, Newborn; Anticonvulsants; Apoptosis; Basal Ganglia; Behavior, Animal; Body Weight; Brain; Dizocilpine Maleate; Electroshock; Levetiracetam; Piracetam; Rats; Rats, Sprague-Dawley; Seizures; Thalamus

Accumulated evidence suggests that actin and microtubule regulating proteins contribute to neuronal structural dynamics, which subsequently affect neuronal plasticity. SCG10 is a neuronal-specific stathmin protein with microtubule destabilizing activity that is affected by multiple phosphorylation, at least in vitro. SCG10 has four major phosphorylation sites: Ser50 and Ser97 targeted by protein kinase A (PKA), and Ser62 and Ser73 targeted by mitogen-activated protein kinase (MAPK). To explore the potential roles of site-specific phosphorylation in physiological models, we developed phosphorylation site-specific antibodies and examined the SCG10 status in primary cultured hippocampal neurons and tissues. Although SCG10 is concentrated in growth cones and the Golgi apparatus in primary cultured neurons, the phosphorylated form was also detected in both regions, suggesting that MT dynamics within the growth cone may be regulated by protein phosphorylation. In the adult hippocampus, an intense stimulus such as kainate treatment induced a rapid phosphorylation of Ser73 within 15 min that was sustained for at least 60 min. This response was mediated through the N-methyl D-aspartic acid (NMDA) receptor and was ablated by the antagonist MK-801. The MAPK enzyme Erk2 was simultaneously activated along a similar time course to SCG10, suggesting that Erk2 may directly phosphorylate Ser73. These results demonstrate that changes in the phosphorylation status of SCG10 in vivo, dependent upon neural activity and/or plasticity, could affect the microtubule dynamics in neuronal dendrites.

Topics: Amino Acid Sequence; Animals; Carrier Proteins; Cells, Cultured; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Electrophoresis, Polyacrylamide Gel; Embryo, Mammalian; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Fluorescent Antibody Technique; Hippocampus; Kainic Acid; Male; Membrane Proteins; Microtubule Proteins; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Nerve Growth Factors; Neurons; Pentylenetetrazole; Peptide Fragments; Phosphorylation; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Serine; Time Factors

Methylmalonic acidemias are metabolic disorders caused by a severe deficiency of methylmalonyl CoA mutase activity, which are characterized by neurological dysfunction, including convulsions. It has been reported that methylmalonic acid (MMA) accumulation inhibits succinate dehydrogenase (SDH) and beta-hydroxybutyrate dehydrogenase activity and respiratory chain complexes in vitro, leading to decreased CO2 production, O2 consumption and increased lactate production. Acute intrastriatal administration of MMA also induces convulsions and reactive species production. Though creatine has been reported to decrease MMA-induced convulsions and lactate production, it is not known whether it also protects against MMA-induced oxidative damage. In the present study we investigated the effects of creatine (1.2-12 mg/kg, i.p.) and MK-801 (3 nmol/striatum) on the convulsions, striatal content of thiobarbituric acid reactive substances (TBARS) and on protein carbonylation induced by MMA. Moreover, we investigated the effect of creatine (12 mg/kg, i.p.) on the MMA-induced striatal creatine and phosphocreatine depletion. Low doses of creatine (1.2 and 3.6 mg/kg) protected against MMA-induced oxidative damage, but did not protect against MMA-induced convulsions. A high dose of creatine (12 mg/kg, i.p.) and MK-801 (3 nmol/striatum) protected against MMA-induced seizures (evidenced by electrographic recording), protein carbonylation and TBARS production ex vivo. Furthermore, acute creatine administration increased the striatal creatine and phosphocreatine content and protected against MMA-induced creatine and phosphocreatine depletion. Our results suggest that an increase of the striatal high-energy phosphates elicited by creatine protects not only against MMA-induced convulsions, but also against MMA-induced oxidative damage. Therefore, since NMDA antagonists are limited value in the clinics, the present results indicate that creatine may be useful as an adjuvant therapy for methylmalonic acidemic patients.

Topics: Animals; Behavior, Animal; Creatine; Dizocilpine Maleate; Electrodes, Implanted; Electroencephalography; Male; Malonates; Microinjections; Neostriatum; Nerve Tissue Proteins; Neuroprotective Agents; Oxidative Stress; Phosphocreatine; Rats; Rats, Wistar; Seizures; Thiobarbituric Acid Reactive Substances

Monosialoganglioside (GM1) is a glycosphingolipid that protects against some neurological conditions, such as seizures and ischemia. Glutaric acidemia type I (GA-I) is an inherited disease characterized by striatal degeneration, seizures, and accumulation of glutaric acid (GA). In this study, we show that GA inhibits Na+,K+-ATPase activity and increases oxidative damage markers (total protein carbonylation and thiobarbituric acid-reactive substances-TBARS) production in striatal homogenates from rats in vitro and ex vivo. It is also shown that GM1 (50 mg/kg, i.p., twice) protects against GA-induced (4 micromol/striatum) seizures, protein carbonylation, TBARS increase, and inhibition of Na+,K+-ATPase activity ex vivo. Convulsive episodes induced by GA strongly correlated with Na+,K+-ATPase activity inhibition in the injected striatum but not with oxidative stress marker measures. Muscimol (46 pmol/striatum), but not MK-801 (3 nmol/striatum) and DNQX (8 nmol/striatum) prevented GA-induced convulsions, increase of TBARS and protein carbonylation and inhibition of Na+,K+-ATPase activity. The protection of GM1 and muscimol against GA-induced seizures strongly correlated with Na+,K+-ATPase activity maintenance ex vivo. In addition, GM1 (50-200 microM) protected against Na+,K+-ATPase inhibition induced by GA (6 mM) but not against oxidative damage in vitro. GM1 also decreased pentylenetetrazole (PTZ)-induced (1.8 micromol/striatum) seizures, Na+,K+-ATPase inhibition, and increase of TBARS and protein carbonyl in the striatum. These data suggest that Na+,K+-ATPase and GABA(A) receptor-mediated mechanisms may play important roles in GA-induced seizures and in their prevention by GM1.

Topics: Animals; Convulsants; Dizocilpine Maleate; Electroencephalography; Excitatory Amino Acid Antagonists; G(M1) Ganglioside; GABA Agonists; Glutarates; Injections, Intraventricular; Male; Muscimol; Neuroprotective Agents; Oxidative Stress; Pentylenetetrazole; Protein Carbonylation; Rats; Rats, Wistar; Receptors, GABA-A; Seizures; Sodium-Potassium-Exchanging ATPase; Thiobarbituric Acid Reactive Substances

In response to harmful stresses, cells induce programmed cell death (PCD) or apoptosis. Seizures can induce neural damage and activate biochemical pathways associated with PCD. Since seizures trigger intracellular calcium overload, it has been presumed that the intrinsic cell death pathway mediated by mitochondrial dysfunction would modulate cell death following seizures. However, previous work suggests that the extrinsic cell death pathway may initiate the damage program. Here we investigate intrinsic versus extrinsic cell death pathway activation using caspase cleavage as a marker for activation of these pathways in a rat in vitro model of seizures. Hippocampal cells, chronically treated with kynurenic acid, had kynurenic acid withdrawn to induce seizure-like activity for 40 min. Subjecting rat hippocampal cultures to seizures increased cell death and apoptosis-like DNA fragmentation using TUNEL staining. Seizure-induced cell death was blocked by both MK801 (10 microM) and CNQX (40 microM), which suggests multiple glutamate receptors regulate seizure-induced cell death. Cleavage of the initiator caspases, caspase 8 and 12 were increased 4h following seizure, and cleavage of the quintessential executioner caspase, caspase 3 was increased 4h following seizure. In contrast, caspase 9 cleavage only increased 24h following seizure. Using an affinity labeling approach to trap activated caspases in situ, we show that caspase 8 is the apical caspase activated following seizures. Finally, we show that the caspase 8 inhibitor Ac-IETD-CHO was more effective at blocking seizure-induced cell death than the caspase 9 inhibitor Ac-LEHD-CHO. Taken together, our data suggests the extrinsic cell death pathway-associated caspase 8 is activated following seizures in vitro.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Caspase 8; Caspase 9; Caspases; Cell Death; Cells, Cultured; Dizocilpine Maleate; DNA Damage; Excitatory Amino Acid Antagonists; Hippocampus; Kynurenic Acid; L-Lactate Dehydrogenase; Neurons; Rats; Rats, Sprague-Dawley; Seizures

Abnormalities of NMDA receptor-mediated neurotransmission are involved in the pathophysiology of schizophrenia, Alzheimer's disease, substance abuse and seizure disorders. The NMDA receptor is implicated in schizophrenia because phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, binds to a hydrophobic domain within the channel, precipitating a schizophreniform psychosis in susceptible persons. Pharmacological, environmental, and genetic variables alter NMDA receptor-mediated neurotransmission. Inbred mouse strains differ in their sensitivity to some of the behavioral effects of MK-801 (dizocilpine), a PCP analogue. The NMDA receptor complex in the BALB/c strain could reflect a unique stoichiometric combination of receptor subunits resulting in a higher proportion of the channels in the open configuration, a higher affinity of MK-801 for its hydrophobic channel domain, and/or a combination of the above. The BALB/c mouse strain, "stressed" mice, and behavioral consequences of MK-801 administration represent models of altered glutamatergic neural transmission. We were interested in examining the effect of stress on the modulatory properties of d-serine and sarcosine. d-Serine is a naturally occurring glycine agonist that modulates the ability of l-glutamate to influence the opening of the NMDA receptor-associated ionophore, and sarcosine is a naturally occurring glycine reuptake inhibitor. The data suggest that 24h after stress, d-serine and sarcosine interact synergistically to reduce MK-801's ability to antagonize electrically precipitated tonic hindlimb extension. Under conditions of stress, modulatory effects of d-serine and sarcosine on the antiseizure effect of MK-801 are observed that are not apparent in the nonstress condition. The results could be relevant to the development of glycinergic interventions for the treatment of neuropsychiatric disorders.

Topics: Analysis of Variance; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Excitatory Amino Acid Antagonists; Male; Mice; Mice, Inbred BALB C; Receptors, N-Methyl-D-Aspartate; Sarcosine; Seizures; Serine; Stress, Physiological; Synaptic Transmission

Methotrexate (MTX)-induced neurotoxicity may occur after intrathecal or systemic administration at low, intermediate and high doses for the treatment of malignant or inflammatory diseases. The mechanisms of MTX neurotoxicity are not totally understood, and appear to be multifactorial. In this study we characterized a model of MTX-induced seizures in mice to evaluate the convulsive and toxic MTX properties. Additionally, the effect of MTX-induced seizures on the activity of glutamate transporters, as well as the anticonvulsant role of MK-801, DNQX and adenosine on glutamate uptake in brain slices was investigated . MTX induced tonic-clonic seizures in approximately 95% of animals and pre-treatment with MK-801, DNQX and adenosine prevented seizure in 80%, 62% and 50% of animals, respectively. Moreover, MTX leads 59% of mice to death, which was prevented in 100% and 94% when animals received MK-801 and DNQX, respectively. Glutamate uptake decreased by 20% to 30% in cortical slices after MTX-induced seizures. Interestingly, when seizures were prevented by MK-801, DNQX or adenosine, glutamate uptake activity remained at the same level as the control group. Thus, our results demonstrate the involvement of the glutamatergic system in MTX-induced seizures.

Topics: Adenosine; Animals; Brain; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Methotrexate; Mice; Neuroprotective Agents; Quinoxalines; Seizures

Mitochondria release proteins that propagate both caspase-dependent and caspase-independent cell death pathways. AIF (apoptosis-inducing factor) is an important caspase-independent death regulator in multiple neuronal injury pathways. Presently, there is considerable controversy as to whether AIF is neuroprotective or proapoptotic in neuronal injury, such as oxidative stress or excitotoxicity. To evaluate the role of AIF in BAX-dependent (DNA damage induced) and BAX-independent (excitotoxic) neuronal death, we used Harlequin (Hq) mice, which are hypomorphic for AIF. Neurons carrying double mutations for Hq/Apaf1-/- (apoptosis proteases-activating factor) are impaired in both caspase-dependent and AIF-mediated mitochondrial cell death pathways. These mutant cells exhibit extended neuroprotection against DNA damage, as well as glutamate-induced excitotoxicity. Specifically, AIF is involved in NMDA- and kainic acid- but not AMPA-induced excitotoxicity. In vivo excitotoxic studies using kainic acid-induced seizure showed that Hq mice had significantly less hippocampal damage than wild-type littermates. Our results demonstrate an important role for AIF in both BAX-dependent and BAX-independent mechanisms of neuronal injury.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Apoptosis; Apoptosis Inducing Factor; Apoptotic Protease-Activating Factor 1; bcl-2-Associated X Protein; Benzodiazepines; Benzothiadiazines; Camptothecin; Caspase Inhibitors; Cells, Cultured; Cerebellum; Cerebral Cortex; Convulsants; Dizocilpine Maleate; Drug Resistance; Flavoproteins; Glutamic Acid; Glycine; Hippocampus; Kainic Acid; Male; Membrane Proteins; Mice; Mice, Knockout; Mice, Mutant Strains; N-Methylaspartate; Neurons; Neurotoxins; Proteins; Proto-Oncogene Proteins c-bcl-2; Recombinant Fusion Proteins; Seizures

The proconvulsive effect of the new generation of antidepressants remains controversial. The authors investigated in naïve rats the effect of chronic treatment with fluoxetine (FLX) on the convulsive threshold and on two parameters of the hippocampal glutamatergic neurotransmission: the in vitro glutamate release and the binding of [3H] MK801 to NMDA receptors. While the acute treatment with FLX provoked no change either in seizure susceptibility or in the glutamate release, the chronic treatment decreased the convulsive threshold in coincidence with an increment in the in vitro glutamate release. No significant effects on the binding of [3H] MK801 to NMDA receptors were found to be attributable to the FLX treatment. We also assessed the effect of the chronic treatment with FLX on the seizure threshold in rats exposed to an experimental model of depression, the learned helplessness paradigm (LH). While a decrease in the K+-stimulated glutamate release was observed in non treated LH animals, when they were chronically injected with FLX, no changes in the epileptic susceptibility and no increments in the glutamate release were found. Our results indicate that chronic treatment with FLX decreases the epileptic threshold in naïve but not in LH rats and that this effect correlates with the levels of the hippocampal glutamate release.

Topics: Animals; Antidepressive Agents, Second-Generation; Behavior, Animal; Convulsants; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Fluoxetine; Glutamic Acid; Helplessness, Learned; Hippocampus; In Vitro Techniques; Male; Pentylenetetrazole; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Synaptic Transmission

Electroconvulsive seizure (ECS) induces structural remodelling in the adult mammalian brain, including an increase in adult hippocampal neurogenesis. The molecular mechanisms that underlie this increase in the proliferation of adult hippocampal progenitors are at present not well understood. We hypothesized that ECS may recruit the Sonic hedgehog (Shh) pathway to mediate its effects on adult hippocampal neurogenesis, as Shh is known to enhance the proliferation of neuronal progenitors and is expressed in the adult basal forebrain, a region that sends robust projections to the hippocampus. Here we demonstrate that the ECS-induced increase in proliferation of adult hippocampal progenitors was completely blocked in animals treated with cyclopamine, a pharmacological inhibitor of Shh signalling. Our results suggest that both acute and chronic ECS enhance Shh signalling in the adult hippocampus, as we observed a robust upregulation of Patched (Ptc) mRNA, a component of the Shh receptor complex and a downstream transcriptional target of Shh signalling. This increase was rapid and restricted to the dentate gyrus, where the adult hippocampal progenitors reside. In addition, both acute and chronic ECS decreased Smoothened (Smo) mRNA, the other component of the Shh receptor complex, selectively within the dentate gyrus. However, ECS did not appear to influence Shh expression within the basal forebrain, the site from which it has been suggested to be anterogradely transported to the hippocampus. Together, our findings demonstrate that ECS regulates the Shh signalling cascade and indicate that the Shh pathway may be an important mechanism through which ECS enhances adult hippocampal neurogenesis.

Topics: Animals; Autoradiography; Bromodeoxyuridine; Cell Count; Dizocilpine Maleate; Electroshock; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Hedgehog Proteins; Hippocampus; Immunohistochemistry; In Situ Hybridization; Male; Neurons; Organogenesis; Patched Receptors; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, G-Protein-Coupled; RNA, Messenger; Seizures; Signal Transduction; Smoothened Receptor; Stem Cells; Time Factors; Trans-Activators; Veratrum Alkaloids

In the present study, the possible role of free radicals in aminophylline-induced seizures was evaluated in albino rats. Aminophylline (theophylline in ethylene diamine; 50 - 300 mg/kg) induced convulsions in rats in a dose-dependent manner, and both incidence of seizure and mortality were maximum at 300 mg/kg. Conventional anti-epileptics, diphenylhydantoin and dizocilpine, as well as adenosine agonists were ineffective in antagonizing these seizures. On the other hand, phosphodiesterase inhibitors, pentoxyphylline and rolipram, showed insignificant seizurogenic effects. Pretreatment with antioxidants (ascorbic acid, alpha-tocopherol, and melatonin) showed differential attenuating effects on aminophylline seizures and lethality. Further, prior administration of 1-buthionine sulfoxamine (BSO, glutathione depletor) and triethyltetramine (TETA, superoxide dismutase inhibitor), precipitated seizures and enhanced lethality in response to subthreshold doses of aminophylline. The present results suggested of the possible involvement of oxidative stress during aminophylline-induced seizures.

Topics: Aminophylline; Animals; Anticonvulsants; Antioxidants; Buthionine Sulfoximine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enzyme Inhibitors; Free Radical Scavengers; Free Radicals; Male; Oxidants; Oxidative Stress; Pentoxifylline; Phenytoin; Phosphodiesterase Inhibitors; Rats; Rats, Wistar; Reactive Oxygen Species; Rolipram; Seizures; Trientine

Repeated cycles of chronic ethanol exposure and withdrawal result in sensitization of withdrawal-related CNS hyperexcitability that generally reflects an imbalance in activity of GABA and glutamate systems. Many pharmacological treatments for ethanol withdrawal target neuroadaptive changes in GABA and glutamate neurotransmission. The present study utilized a mouse model of repeated withdrawals to evaluate the ability of lorazepam and MK-801 treatments to antagonize behavioral and electroencephalographic (EEG) measures of sensitized withdrawal seizure activity. Adult male C3H/He mice received chronic intermittent ethanol vapor exposure in inhalation chambers (16 h/day) and during each withdrawal cycle, separate groups of mice were evaluated for handling-induced convulsions (HIC) or abnormal EEG (high-voltage "brief spindle episodes" (BSE)) activity. Lorazepam (0.5-1.0 mg/kg) or MK-801 (0.1-0.3 mg/kg) treatment at 1 h into each of three withdrawal cycles reduced behavioral (HIC) and electrographic (BSE) signs of seizure activity in a dose-related fashion compared to vehicle-treated mice. During a subsequent untreated withdrawal, mice previously treated with lorazepam or MK-801 for earlier withdrawals exhibited reduced HIC activity during the acute phase but exacerbated HIC activity during the protracted phase of this final (fourth) withdrawal cycle. Both lorazepam and MK-801 treatment conditions resulted in enhanced BSE activity during the entire fourth (untreated) withdrawal episode. Collectively, these results suggest that while treatment of repeated ethanol withdrawals with a benzodiazepine (lorazepam) or an NMDA receptor antagonist (MK-801) may have some initial benefits in ameliorating the development of sensitized withdrawal excitability, such treatment may also render subjects more vulnerable to seizure activity at later time points.

Topics: Animals; Area Under Curve; Behavior, Animal; Central Nervous System Depressants; Dizocilpine Maleate; Electrodes; Electroencephalography; Electrophysiology; Ethanol; Excitatory Amino Acid Antagonists; GABA Modulators; Handling, Psychological; Hyperkinesis; Lorazepam; Male; Mice; Mice, Inbred C3H; Seizures; Substance Withdrawal Syndrome

Rapid administration of large doses of ammonia leads to death of animals, which is largely prevented by pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists. The present study focuses on a subunit(s) of NMDA receptor involved in ammonia-induced death by use of NMDA receptor GluRepsilon subunit-deficient (GluRepsilon(-/-)) mice and the selective GluRepsilon2 antagonist CP-101,606. Acute ammonia intoxication was induced in mice (eight per group) by a single intraperitoneal (i.p.) injection of ammonium chloride. Appearance of neurological deteriorations depended on the doses of ammonium chloride injected. While wild-type, GluRepsilon1(-/-), GluRepsilon4(-/-), and GluRepsilon1(-/-)/epsilon4(-/-) mice all died by ammonium chloride at 12 mmol/kg during the first tonic convulsions, two of eight GluRepsilon3(-/-) mice survived. Pretreatment of wild-type mice with CP-101,606 prevented two mice from ammonia-induced death. Pretreatment of GluRepsilon3(-/-) mice with CP-101,606 prevented the death of three mice and prolonged the time of death of non-survivors. Similarly, the neuronal form of nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI) as well as the nonselective NOS inhibitor L-NMMA, but not the inducible NOS inhibitor 1400W, partially prevented the death of mice and prolonged the period of death. Furthermore, ammonium chloride prolonged the increase in intracellular free Ca2+ concentration ([Ca2+]i) and subsequent NO production induced by NMDA in the cerebellum. These results suggest that activation of NMDA receptor containing GluRepsilon2 and GluRepsilon3 subunits and following activation of neuronal NOS are involved in acute ammonia intoxication which leads to death of animals.

Topics: Ammonia; Animals; Calcium; Cerebellum; Coma; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Piperidines; Receptors, N-Methyl-D-Aspartate; Seizures

The present study was designed to examine the effect of agmatine, the decarboxylated product of L-arginine by L-arginine decarboxylase, on convulsion in the mouse maximal electroshock (MES) test and mouse glutamate-induced convulsant test. MES convulsion and glutamate convulsion were respectively induced by an electrical stimulation (110 V, 0.3 s, 8 Hz) and by intracerebroventricular injection of glutamate (0.5 M, pH 7.4, 5microl). The results were expressed as the tonic and clonic time of convulsion in MES or percentage of mice with tonic hind-limb extension in glutamate-induced convulsant assay. Agmatine given intracerebroventricularly (2-16 mg/kg) or subcutaneously (10-160 mg/kg) significantly shortened the tonic and clonic times of convulsion in a dose-dependent manner in the mouse MES test. Glutamate (0.5 M, 5microl icv per mouse) induced an obvious convulsive response indicated by tonic hind-limb extension in mice, and agmatine (2-16 mg/kg icv) decreased the rate of mice with tonic hind-limb extension like NMDA receptor antagonist MK-801. The anticonvulsive effect of agmatine (80 mg/kg sc) on both the tonic and clonic times of convulsion lasted for more than 4 h after administration in the mouse MES test, which was twice that of barbital. Taken together, the results implicate that agmatine has obvious anticonvulsive effects, and its possible mechanism might be related to the antagonism of the function of NMDA receptors.

Topics: Agmatine; Animals; Anticonvulsants; Dizocilpine Maleate; Electroshock; Excitatory Amino Acid Antagonists; Glutamic Acid; Injections, Intraventricular; Male; Mice; Receptors, N-Methyl-D-Aspartate; Seizures

Such organophosphorus (OP) compounds as diisopropylfluorophosphate (DFP), sarin and soman are potent inhibitors of acetylcholinesterases (AChEs) and butyrylcholinesterases (BChEs). The acute toxicity of OPs is the result of their irreversible binding with AChEs in the central nervous system (CNS), which elevates acetylcholine (ACh) levels. The protective action of subcutaneously (SC) administered antidotes or their combinations in DFP (2.0 mg/kg BW) intoxication was studied in 9-10-weeks-old Han-Wistar male rats. The rats received AChE reactivator pralidoxime-2-chloride (2PAM) (30.0 mg/kg BW), anticonvulsant diazepam (2.0 mg/kg BW), A(1)-adenosine receptor agonist N(6)-cyclopentyl adenosine (CPA) (2.0 mg/kg BW), NMDA-receptor antagonist dizocilpine maleate (+-MK801 hydrogen maleate) (2.0 mg/kg BW) or their combinations with cholinolytic drug atropine sulfate (50.0 mg/kg BW) immediately or 30 min after the single SC injection of DFP. The control rats received atropine sulfate, but also saline and olive oil instead of other antidotes and DFP, respectively. All rats were terminated either 24 h or 3 weeks after the DFP injection. The rats treated with DFP-atropine showed severe typical OP-induced toxicity signs. When CPA, diazepam or 2PAM was given immediately after DFP-atropine, these treatments prevented, delayed or shortened the occurrence of serious signs of poisoning. Atropine-MK801 did not offer any additional protection against DFP toxicity. In conclusion, CPA, diazepam and 2PAM in combination with atropine prevented the occurrence of serious signs of poisoning and thus reduced the toxicity of DFP in rat.

Topics: Acetylcholinesterase; Adenosine; Animals; Antidotes; Atropine; Brain; Cholinesterase Inhibitors; Diazepam; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; GABA Modulators; Isoflurophate; Lung; Male; Nerve Tissue Proteins; Organophosphorus Compounds; Pralidoxime Compounds; Rats; Rats, Wistar; Seizures

The combined effects of physostigmine and procyclidine (antagonizing muscarinic, nicotinic, and NMDA receptors) were tested against various doses of soman. Physostigmine (0.1 mg/kg) in combination with procyclidine doses of 1, 3, or 6 mg/kg effectively prevented the development of convulsions and hippocampally monitored seizures when the doses of soman were 1.3, 1.6, or 2 x LD50, respectively. Results from [(3)H]MK-801-binding experiments showed that procyclidine inhibits the phencyclidine site at the NMDA receptor in a concentration-dependent manner. Physostigmine (0.1 mg/kg) and procyclidine in a dose of 1 mg/kg did not prevent convulsions or seizures when the soman dose was 1.6 x LD50. Subsequent treatment with scopolamine in doses of 0.5 or 1 mg/kg immediately after (3 min) seizure onset showed that only the highest dose produced a reliable termination. When scopolamine (1 mg/kg) was given later (10 min) after onset of seizures, no effect was obtained. The sustained seizures were subsequently treated with diazepam (10 mg/kg) and pentobarbital (30 mg/kg) and finally terminated 25 min after onset. In rats given inadequate prophylaxis, both modified convulsions and seizures were seen. It is suggested that moderate doses of prophylactics should be preferred to avoid adverse effects on cognitive functions because insufficient prophylaxis can be compensated for by adjunct treatment.

Topics: Animals; Cholinesterase Inhibitors; Convulsants; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroencephalography; Hippocampus; Male; Muscarinic Antagonists; Neuroprotective Agents; Physostigmine; Procyclidine; Rats; Rats, Wistar; Scopolamine; Seizures; Soman

Succinate is a dicarboxylic acid that accumulates due to succinate dehydrogenase inhibition by malonate and methylmalonate exposure. These neurotoxins cause increased excitability and excitotoxic damage, which can be prevented by administering high amounts of succinate. In the present study we investigated whether succinate alters hippocampal field excitatory post-synaptic potentials. Bath application of succinate at intermediate concentrations (0.3-1 mM) increased the slope of field excitatory post-synaptic potentials in hippocampal slices, and at high concentrations (above 1 mM) did not alter or decrease field excitatory post-synaptic potentials slope. Succinate-induced enhancement of field excitatory post-synaptic potentials slope was abolished by the addition of d-2-amino-5-phosphonovaleric acid (50 microM) to the perfusate, supporting the involvement of N-methyl-d-aspartate receptors in the excitatory effect of this organic acid. Accordingly, succinate (0.8-7.5 micromol) i.c.v. administration caused dose-dependent convulsive behavior in mice. The i.c.v. co-administration of MK-801 (7 nmol) fully prevented succinate-induced convulsions, further suggesting the involvement of N-methyl-d-aspartate receptors in the convulsant action of succinate. Our data indicate that accumulation of moderate amounts of succinate may contribute to the excitotoxicity induced by succinate dehydrogenase inhibitors, through the activation of N-methyl-d-aspartate receptors.

Topics: Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Hippocampus; Injections, Intraventricular; Male; Mice; Neurons; Neuroprotective Agents; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Succinic Acid

N-methyl D-aspartate (NMDA) preconditioning has been used to prevent cellular death induced by glutamate or NMDA in cultured neurons. Quinolinic acid (QA)-induced seizures are used to average NMDA receptors-evoked neurotoxicity in animal models. The purpose of this study was to investigate the potential neuroprotective effects of NMDA preconditioning against QA-induced seizures and hippocampal damage in vivo.. Mice were pretreated with nonconvulsant doses of NMDA for different times before i.c.v. QA infusion and observed for the occurrence of seizures. Hippocampal slices from mice were assayed to measure cellular viability.. NMDA preconditioning presented 53% protection against QA-induced seizures, as well as QA-induced cellular death in the hippocampus. The NMDA receptor antagonist, MK-801, prevented the protection evoked by NMDA preconditioning. The adenosine A1 receptor antagonist, CPT, prevented the protection evoked by NMDA preconditioning against QA-induced seizures, but not against QA-induced hippocampal cellular damage. The adenosine A1 receptor agonist, CPA, did not mimic the NMDA preconditioning-evoked protective effects.. These results suggest that in vivo preconditioning with subtoxic doses of NMDA protected mice against seizures and cellular hippocampal death elicited by QA, probably through mechanisms involving NMDA receptors operating with adenosine A1 receptors.

Topics: Animals; Apoptosis; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Hippocampus; Humans; Male; Mice; Motor Activity; N-Methylaspartate; Neurons; Neurotoxicity Syndromes; Quinolinic Acid; Receptors, N-Methyl-D-Aspartate; Seizures

Dendritic targeting of mRNA and local protein synthesis are mechanisms that enable neurons to deliver proteins to specific postsynaptic sites. Here, we demonstrate that epileptogenic stimuli induce a dramatic accumulation of BDNF mRNA and protein in the dendrites of hippocampal neurons in vivo. BDNF mRNA and protein accumulate in dendrites in all hippocampal subfields after pilocarpine seizures and in selected subfields after other epileptogenic stimuli (kainate and kindling). BDNF accumulates selectively in discrete dendritic laminas, suggesting targeting to synapses that are active during seizures. Dendritic targeting of BDNF mRNA occurs during the time when the cellular changes that underlie epilepsy are occurring and is not seen after intense stimuli that are non-epileptogenic, including electroconvulsive seizures and high-frequency stimulation. MK801, an NMDA receptor antagonist that can prevent epileptogenesis but not acute seizures, prevents the dendritic accumulation of BDNF mRNA, indicating that dendritic targeting is mediated via NMDA receptor activation. Together, these results suggest that dendritic accumulation of BDNF mRNA and protein plays a critical role in the cellular changes leading to epilepsy.

Topics: Animals; Biological Transport; Brain-Derived Neurotrophic Factor; Cell Compartmentation; Convulsants; Dendrites; Dizocilpine Maleate; Electroshock; Epilepsy; Hippocampus; Kainic Acid; Kindling, Neurologic; Male; Pilocarpine; Protein Transport; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Seizures; Status Epilepticus; Synapses

Seizures have been shown to promote the proliferation of granule cell precursors in the adult brain, but the underlying mechanisms remain largely unknown. Using systemic bromodeoxyuridine (BrdU) to label dividing cells, we examined the effects of selective ionotropic glutamate receptor antagonists on granule cell precursor proliferation in adult rats after pentylenetrazol (PTZ)-induced generalized clonic seizures. We found that the NMDA receptor antagonist MK-801 significantly inhibited behavioral and EEG seizures and completely blocked seizure-induced increase in the number of BrdU-labeled cells in the dentate gyrus. Although the AMPA/KA receptor antagonist DNQX was not observed to affect seizures, it significantly suppressed the number of BrdU-labeled cells in the dentate gyrus. Double immunohistochemical staining showed that both the mature granule cells and the majority of BrdU-labeled, mitotically active cells expressed the NMDA receptor subunit NR1 and the AMPA/KA receptor subunit GluR2. Because accumulated evidence showed that mild seizures are sufficient to promote precursor cell proliferation, the present findings that MK-801 inhibited seizures and completely blocked seizure-induced increase in precursor cell proliferation suggest that the direct blockade action of MK-801 on NMDA receptors on the granule cell precursors may play an important role in blocking seizure-induced precursor cell proliferation. The suppression of seizure-induced proliferation of granule cell precursors by DNQX may be achieved by the direct action of DNQX on AMPA/KA receptors on the granule cell precursors. Thus, our findings indicate that seizures may promote cell proliferation in the adult rat dentate gyrus through glutamatergic mechanisms acting on both NMDA and AMPA/KA receptors.

Topics: Animals; Cell Count; Cell Proliferation; Dentate Gyrus; Dizocilpine Maleate; Down-Regulation; Excitatory Amino Acid Antagonists; Male; Neurons; Pentylenetetrazole; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Seizures; Stem Cells

The present study evaluated the potential effect of geranylgeranylacetone (GGA), which is known as an antiulcer agent, against kainic acid (KA)-induced neurotoxicity. Pretreatment with a single oral GGA dose (800 mg/kg, 2 days before KA) significantly attenuated KA-induced seizures and cell death in rat hippocampus. These effects of GGA were prevented by the coinjection of MK801, a noncompetitive N-methyl-D-aspartate glutamate receptor antagonist, which indicates that the protection was indeed mediated by glutamate receptor activation.

Topics: Administration, Oral; Animals; Anti-Ulcer Agents; Cell Death; Convulsants; Diterpenes; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Kainic Acid; Male; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Seizures

Zac1, a new zinc-finger protein that regulates both apoptosis and cell cycle arrest, is abundantly expressed in many proliferative/differentiation areas during brain development. In the present work, we studied Zac1 gene expression and protein in experimental seizure models following i.p. injection of pentylenetetrazole (PTZ) or kainic acid (KA). Following KA treatment, an early and intense up-regulation of Zac1 is detected in the limbic areas, such as the hippocampus, cortex and amygdaloid and hypothalamic nuclei. Pre-treatment with MK-801, an antagonist of the NMDA receptors, fully blocks the effect of KA in the hippocampus, whereas it only attenuates KA-induced Zac1 up-regulation in the other areas of the limbic system. A reduced induction is obtained with PTZ-treated animals, specifically in the entorhinal and piriform cortices as well as in amygdaloid and hypothalamic nuclei. Thus, Zac1 is highly induced in the seizure models that generate strong neuronal stimulation and/or extensive cell damage (cell death), reinforcing its putative role in the control of the cell cycle and/or apoptosis. Moreover, strong induction is observed in the granular cells of the dentate gyrus (which are resistant to neurodegeneration) and in some glial cells of the dentate gyrus and subventricular zone, suggesting that Zac1 may be implicated in the mechanisms of neural plasticity following injury.

Topics: Animals; Apoptosis; Cell Cycle Proteins; Convulsants; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Gene Expression; Genes, Tumor Suppressor; Glial Fibrillary Acidic Protein; Immunohistochemistry; Kainic Acid; Limbic System; Male; Mice; Mice, Inbred ICR; Neurons; Pentylenetetrazole; Proto-Oncogene Proteins c-fos; RNA, Messenger; Seizures; Tissue Distribution; Transcription Factors; Zinc Fingers

Alterations in hippocampal neuronal Ca(2+) and Ca(2+)-dependent systems have been implicated in mediating some of the long-term neuroplasticity changes associated with acquired epilepsy (AE). However, there are no studies in an animal model of AE that directly evaluate alterations in intracellular calcium concentration ([Ca(2+)](i)) and Ca(2+) homeostatic mechanisms (Ca(2+) dynamics) during the development of AE. In this study, Ca(2+) dynamics were evaluated in acutely isolated rat CA1 hippocampal, frontal, and occipital neurons in the pilocarpine model by using [Ca(2+)](i) imaging fluorescence microscopy during the injury (acute), epileptogenesis (latency), and chronic-epilepsy phases of the development of AE. Immediately after status epilepticus (SE), hippocampal neurons, but not frontal and occipital neurons, had significantly elevated [Ca(2+)](i) compared with saline-injected control animals. Hippocampal neuronal [Ca(2+)](i) remained markedly elevated during epileptogenesis and was still elevated indefinitely in the chronic-epilepsy phase but was not elevated in SE animals that did not develop AE. Inhibiting the increase in [Ca(2+)](i) during SE with the NMDA channel inhibitor MK801 was associated in all three phases of AE with inhibition of the changes in Ca(2+) dynamics and the development of AE. Ca(2+) homeostatic mechanisms in hippocampal neurons also were altered in the brain-injury, epileptogenesis, and chronic-epilepsy phases of AE. These results provide evidence that [Ca(2+)](i) and Ca(2+)-homeostatic mechanisms are significantly altered during the development of AE and suggest that altered Ca(2+) dynamics may play a role in the induction and maintenance of AE and underlie some of the neuroplasticity changes associated with the epileptic phenotype.

Topics: Animals; Apoptosis; Calcium; Dizocilpine Maleate; Epilepsy; Hippocampus; Homeostasis; Male; Neurons; Rats; Rats, Sprague-Dawley; Seizures; Time Factors

Hypoxia of the brain may alter further seizure susceptibility in a different way. In this study, we tried to answer the question how episode of convulsion induced by hypoxia (HS) changes further seizure susceptibility, and how N-methyl-D-aspartic acid (NMDA) and AMPA/KA receptor antagonists influence this process. Adult Albino Swiss mice exposed to hypoxia (5% O(2)) developed clonic/tonic convulsions after about 340 s. Mice which underwent 10 s but not 5 s seizures episode subsequently exhibited significantly increased seizure susceptibility to low doses (equal ED(16)) of bicuculline (BCC) and NMDA during a 3-week observation period. No morphological signs of brain tissue damage were seen in light microscope on the third day after a hypoxia-induced seizure (HS). Learning abilities assessed in passive avoidance test as well as spontaneous alternation were not disturbed after an HS episode. Pretreatment with AMPA/KA receptor antagonist NBQX effectively prolonged latency to HS and given immediately after seizure episode also attenuated subsequent convulsive susceptibility rise, however, NMDA receptor antagonist, MK-801, appeared to be ineffective. These results suggest that a seizure episode induced by hypoxia, depending on its duration, may play an epileptogenic role. The AMPA/KA receptor antagonist prolongs the latency to HS, and given after this episode, prevents the long-term epileptogenic effect.

Topics: Animals; Avoidance Learning; Bicuculline; Brain Chemistry; Dizocilpine Maleate; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; GABA Antagonists; gamma-Aminobutyric Acid; Hypoxia; Mice; N-Methylaspartate; Quinoxalines; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Seizures

The development of tolerance to therapeutic effects of antiepileptic drugs can be a problem in the treatment of epilepsy, bipolar disorder, and pain syndromes. In the present study, acute treatment with the new antiepileptic drug lamotrigine (LTG, 15 mg/kg) markedly suppressed seizure stage and seizure duration in amygdala-kindled rats; but this antiseizure effect was rapidly lost following 4-8 days of repeated treatment. When gabapentin (GBP, 20 mg/kg) was coadministered with LTG, the ability of LTG to suppress seizure stage, seizure duration, and after-discharge (AD) duration was markedly extended. In addition, GBP coadministration with LTG decreased the number of animals that developed LTG-related running fits (Stage 6 seizures) and lengthened the number of days required to develop running fits or complete tolerance. Neither acute nor repeated treatment with MK-801 (0.3 mg/kg), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, had effects on kindled seizures. However, cotreatment with MK-801 markedly extended the anticonvulsant effects of LTG on the three seizure indices and reduced running fits. These data indicate that cotreatment with either GBP or MK-801 slows tolerance development to the anticonvulsant effects of LTG on kindled seizures. Therapeutic implications of the present study remain to be explored.

Topics: Acetates; Amines; Animals; Anticonvulsants; Cyclohexanecarboxylic Acids; Dizocilpine Maleate; Drug Therapy, Combination; Drug Tolerance; Gabapentin; gamma-Aminobutyric Acid; Kindling, Neurologic; Lamotrigine; Male; Rats; Rats, Sprague-Dawley; Seizures; Triazines

Mice were administered anticholinesterase pesticides dichlorvos (DDVP) or methomyl (MET). Both DDVP and MET induced dose-dependent seizures and lethality in mice. The muscarinic antagonist atropine (ATR, 1.8 mg/kg) did not prevent seizures but diminished the lethality induced by DDVP or MET. The nicotinic antagonist mecamylamine (MEC, 1 mg/kg) affected neither DDVP-induced seizures nor DDVP- and MET-induced lethality, but diminished MET-induced seizures. At a higher dose (10 mg/kg), MEC attenuated seizures produced by MET, but not DDVP, and decreased lethality of both anticholinesterases. The N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801, 1 mg/kg) prevented DDVP-, but not MET-induced seizures. MK-801 did not affect DDVP- or MET-induced lethality. Concurrent administration of ATR and MK-801 prevented the occurrence of DDVP- but not MET-induced seizures. MK-801 coadministered with ATR enhanced its protective effect against DDVP- or MET-induced lethality in mice. Coinjection of MEC (at both doses studied) and MK-801 completely prevented seizures produced by both acetylcholinesterase (AChE) inhibitors. Coadministration of MEC (1 mg/kg) and MK-801 protected mice against DDVP or MET lethality. MK-801 administered along with MEC at 10 mg/kg enhanced antilethal effects of the nicotinic antagonist in DDVP- or MET-treated mice. With respect to the mechanism underlying anticholinesterase-induced neurotoxicity, muscarinic and nicotinic, as well as NMDA receptors, seem to play major roles. The results suggest that combined treatment with cholinergic and NMDA antagonists might be beneficial in anticholinesterase-induced poisonings.

Topics: Animals; Cholinergic Antagonists; Cholinesterase Inhibitors; Dichlorvos; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Antagonists; Insecticides; Lethal Dose 50; Male; Methomyl; Mice; Seizures

The effects of acute and repeated administration of MK-801 on flurothyl (FE)-induced seizure were investigated in mice. In the acute effect of MK-801 (0.01-0.1 mg/kg ip) in naive and FE-kindled mice, there were no changes on the latencies of clonic seizures. However, MK-801 dose-dependently inhibited both latencies and incidence of tonic seizures in mice and suppressed the grade of seizure severity in FE-kindled mice. Repeated administration of MK-801 at doses of 0.01 and 0.1 mg/kg 2 h prior to each exposure to FE for 8 days did not show any effects on the latencies of clonic seizure. However, seizure severity was significantly exacerbated in the 0.1 mg/kg treated group when mice were re-exposed to FE without MK-801 1 week after the last administration. A week after the repeated administration of MK-801 at a dose of 0.1 mg/kg for 8 days without exposure to FE, mice were exposed to FE 2 h after readministration of MK-801 until tonic seizure occurred. The latencies of clonic seizures were almost the same in the acute experiment in naive controls. The latency of tonic seizure was significantly delayed compared to the acute experiment with MK-801 at a dose of 0.1 mg/kg. These findings suggested that MK-801 possessed an anticonvulsant action against FE-induced tonic seizure. However, the efficacy of this acute effect of MK-801 was impaired at 1 week of withdrawal after repeated administrations. This may be related in part to the changes in sensitivity to NMDA receptors.

Topics: Animals; Anticonvulsants; Dizocilpine Maleate; Dose-Response Relationship, Drug; Flurothyl; Male; Mice; Mice, Inbred C57BL; Seizures

Methylmalonic acidemias are metabolic disorders caused by a severe deficiency of methylmalonyl-CoA mutase activity, which are characterized by neurological dysfunction, including convulsions. It has been reported that the accumulating metabolite, L-methylmalonic acid (MMA), inhibits succinate dehydrogenase leading to ATP depletion in vitro, and that the intrastriatal injection of MMA induces convulsions through secondary NMDA receptor stimulation. In this study we investigated the effect of creatine (1.2, 3.6 and 12.0 mg/kg, (i.p.), [DOSAGE ERROR CORRECTED] succinate (1.5 micromol/striatum) and MK-801 (3 nmol/striatum) on the convulsions and on the striatal lactate increase induced by MMA (4.5 micromol/striatum) in rats. The effect of creatine on the striatal phosphocreatine content and on MMA-induced phosphocreatine depletion was also evaluated. Creatine, succinate and MK-801 pretreatment decreased the number and duration of convulsive episodes and the lactate increase elicited by MMA. Creatine, but not succinate, prevented the convulsions and the lactate increase induced by the direct stimulation of NMDA receptors. Acute creatine administration increased the total striatal phosphocreatine content and prevented MMA-induced phosphocreatine depletion. Our results suggest that MMA increases lactate production through secondary NMDA receptor activation, and it is proposed that the anticonvulsant effect of creatine against MMA-induced convulsions may be due to an increase in the phosphocreatine content available for metabolic purposes.

Topics: Animals; Behavior, Animal; Corpus Striatum; Creatine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Lactic Acid; Male; Methylmalonic Acid; N-Methylaspartate; Phosphocreatine; Radiation-Protective Agents; Rats; Rats, Wistar; Seizures; Succinic Acid

The ability of mono- and dicationic phenylcyclohexyl derivatives, which are non-competitive glutamate antagonists, to prevent convulsions induced in mice by intragastric NMDA or kainate, to weaken catalepsy induced in rats by haloperidol and to exert their own influences of movement activity and behavior in animals was studied. The actions of study compounds were compared with those of the known NMDA antagonists memantine and dizocilpine. NMDA-induced convulsions were effectively prevented by both mono- and dications, while only dications were effective against kainate convulsions. Anticataleptic activity was significantly more marked in monocations, which lacked the ability to block non-NMDA receptors. Side effects on motor coordination were less marked with study compounds than with dizocilpine. Thus, the effects of phenylcyclohexyl derivatives in in vivo experimental models correlate with their anti-NMDA and anti-AMPA activity. They can be regarded as potential agents for treating parkinsonism and other motor disorders.

Topics: Animals; Ataxia; Behavior, Animal; Catalepsy; Diamines; Disease Models, Animal; Dizocilpine Maleate; Dopamine Antagonists; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Haloperidol; Kainic Acid; Memantine; Mice; Mice, Inbred Strains; N-Methylaspartate; Quaternary Ammonium Compounds; Seizures; Structure-Activity Relationship; Time Factors

This study investigated whether D,L-cis-2,3-Pyrrolidine dicarboxylate (D,L-cis-2,3-PDC), a new glutamate analogue, alters glutamate binding to cerebral plasma membranes and whether N-methyl-D-aspartate (NMDA) receptors are involved in the convulsant effect of this compound. D,L-cis-2,3-PDC reduced sodium-independent [3H]-L-glutamate binding to lysed membrane preparations from adult rat cortex and had no effect on sodium-dependent glutamate binding. Intracerebroventricular administration of D,L-cis-2,3-PDC (7.5-25 nmol/5 microl) induced generalized tonic-clonic convulsions in mice in a dose-dependent manner. The coadministration of MK-801 (7 nmol/2.5 microl), with D,L-cis-2,3-PDC (16.5 nmol/2.5 microl), fully protected the animals against D,L-cis-2,3-PDC-induced convulsions, while the coadministration of DNQX (10 nmol/2.5 microl) increased the latency to convulsions but did not alter the percentage of animals that had convulsions. These results suggest that D,L-cis-2,3-PDC-induced effects are mediated predominantly by NMDA receptors.

Topics: Animals; Behavior, Animal; Brain Chemistry; Convulsants; Dicarboxylic Acids; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Membranes; Mice; Neuroprotective Agents; Pyrrolidines; Quinoxalines; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Stereoisomerism; Structure-Activity Relationship

Mutations in ion channels, or channelopathies, often lead to neurological disorders in which normal behavior is interrupted by attacks of debilitating symptoms such as pain, weakness or abnormal motor control. Attacks are often precipitated by similar stimuli, including stress, caffeine, ethanol, exercise or fatigue. The tottering mouse inherits a mutation in P/Q-type calcium channels and reliably exhibits attacks of abnormal movements, or dyskinesia. To determine if this mouse mutant is an appropriate model to study episodic neurological disorders, tottering mice were exposed to different environmental conditions or drugs known to precipitate attacks in humans. Stress, caffeine and ethanol all reliably induced attacks in tottering mice. Since calcium influx has previously been implicated in stress-induced tottering mouse attacks, the L-type calcium channel antagonist, nimodipine, and the NMDA receptor antagonist, MK 801, were tested for their ability to prevent attacks caused by caffeine or ethanol administration. Nimodipine blocked both caffeine- and ethanol-induced attacks, while MK 801 was effective against stress- and caffeine-induced attacks. These results support a common role for excess neuronal excitability and increased calcium influx in attacks triggered by diverse agents. Together, these results suggest that the tottering mouse is a novel model to investigate triggers of episodic neurological disorders.

Topics: Animals; Anticonvulsants; Caffeine; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Signaling; Central Nervous System Stimulants; Chorea; Dizocilpine Maleate; Dose-Response Relationship, Drug; Environment; Excitatory Amino Acid Antagonists; Lighting; Mice; Mice, Neurologic Mutants; Nimodipine; Receptors, N-Methyl-D-Aspartate; Restraint, Physical; Seizures; Stress, Psychological

A majority of beta-lactam antibiotics (e.g., cephalosporins and penicillins) have convulsive activity to a greater or lesser extent. (6R,7R)-3-[[3-Amino-2-(2-hydroxyethyl)-2H-pyrazol-1-ium-1-yl]methyl]-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate monosulfate (cefoselis), a newly developed injectable beta-lactam antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA), might induce convulsions if cerebral concentrations become highly elevated. In the present study, we examined whether or not cefoselis had convulsive activity after direct brain administration, and we attempted to clarify the pharmacological mechanism of action. When cefoselis was injected into the lateral ventricle of the mouse brain at doses higher than 20 microg/animal, it produced convulsions dose-dependently. Cefoselis (50 microg/animal)-induced convulsions were prevented by pretreatment with 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), diazepam and phenobarbital (ED(50) values (mg/kg) of 0.78, 1.59 and 33.0, respectively), but not by carbamazepine or phenytoin. When the effects of these anticonvulsants on the convulsions induced by intracerebral injection of bicuculline methiodide (BMI) or N-methyl-D-aspartate (NMDA) were investigated, the inhibitory profile of anticonvulsants on cefoselis-induced convulsions was similar to those induced by BMI (125 ng/animal) but differed markedly in their inhibitory activity on NMDA (100 ng/animal)-induced convulsions, which were not inhibited by diazepam. These results suggest that cefoselis may be convulsive at higher concentrations through a mechanism involving inhibition of gamma-aminobutyric acid (GABA)(A) receptors.

Topics: Animals; Anti-Bacterial Agents; Anticonvulsants; Bicuculline; Carbamazepine; Ceftizoxime; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; GABA Antagonists; GABA Modulators; GABA-A Receptor Agonists; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; N-Methylaspartate; Phenobarbital; Phenytoin; Receptors, GABA; Seizures; Sodium Channel Blockers

The aim of this study was to evaluate the neuroprotective effect of CHF3381, a novel putative NMDA antagonist characterized by a good therapeutic index. We have compared the effects of CHF3381 on kainate seizure-induced neurodegeneration with those produced by the non competitive NMDA receptor antagonist MK-801 and by the Na channel blocker lamotrigine. All compounds have been employed at doses incapable of preventing or attenuating seizures. The fluorescent marker Fluoro-Jade B has been used to identify degenerating cells. Animals pretreated with lamotrigine presented the same degree of cell damage as the controls. As for the controls, a clear correlation was also observed between seizure severity and neurodegeneration. In contrast, MK-801 and CHF3381 completely prevented cell damage. These data indicate that CHF3381 may be successfully utilized in neurological disorders characterized by or associated with neurodegenerative excitotoxicity.

Topics: Animals; Anticonvulsants; Cell Death; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glycine; Hippocampus; Histological Techniques; Indans; Kainic Acid; Lamotrigine; Male; Mice; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Seizures; Triazines

Phosphinothricin (PPT), the active component of a widely used herbicide, induces convulsions in rodents and humans. PPT shares structural analogy with glutamate, which could explain its powerful inhibitory effect on glutamine synthetase and its probable binding to glutamate receptors. To characterize the epileptogenic effect of PPT, electrographic and behavioural studies were carried out on PPT-treated adult mice. We investigated the role of N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide (NO) production in induction of seizures triggered by PPT, by using specific NMDA antagonist and nitric oxide synthase (NOS) inhibitor. The inhibitory effect of PPT on glutamine synthetase of mouse brain was assessed after in vitro and in vivo treatments. The results obtained show that PPT induces tonic-clonic seizures and generalized convulsions in mice. They suggest that these seizures are mediated through an NMDA receptor activation and NO production, without involvement of inhibition of glutamine synthetase.

Topics: Aminobutyrates; Animals; Brain; Dizocilpine Maleate; Electroencephalography; Enzyme Inhibitors; Epilepsy; Excitatory Amino Acid Antagonists; Glutamate-Ammonia Ligase; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Receptors, N-Methyl-D-Aspartate; Seizures

The crude extract from the sea anemone, Bunodosoma caissarum caused dose-dependent convulsions by i.c.v. route in mice. The involvement of the glutamatergic system in the convulsions was investigated. MK-801 and ketamine, non-competitive NMDA receptor antagonists, prolonged the latencies for convulsion onset. AP-5, a competitive NMDA receptor antagonist, reduced the number of animals convulsing and also increased the latency for convulsion onset. 7-Chlorokynurenic acid, an antagonist of the glycine site on the NMDA receptor, reduced the incidence of convulsions. GMP, a nucleotide known to antagonize some NMDA actions, reduced the incidence and the severity of convulsions and prolonged the latency for their onset. Riluzole, a neuroprotective and anticonvulsant agent, blocked the appearance of convulsions. In vitro, the crude extract inhibited [3H]glutamate binding to cerebral cortical membranes and enhanced [3H]glutamate release from cortical synaptosomes. Heating the crude extract to 100 degrees C for 30 min or preincubating it with sphingomyelin, abolished its effect on glutamate release, but did not alter its ability to induce convulsions and to inhibit glutamate binding. However, the convulsant action was inhibited when the crude extract was submitted to trypsin treatment. Our data suggest that the convulsions elicited by the crude extract are not due to the presence of cytolysin and are not related to an increase in glutamate release, but seem to be dependent on the interaction between a peptide component of the extract and NMDA receptors.

Topics: Animals; Cerebral Cortex; Cnidarian Venoms; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; In Vitro Techniques; Injections, Intraventricular; Ketamine; Reaction Time; Receptors, N-Methyl-D-Aspartate; Sea Anemones; Seizures; Synaptosomes; Trypsin

Dizocilpine maleate (MK-801) is a highly potent, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Although it has been suggested that dizocilpine may be beneficial in alleviating some symptoms of ethanol withdrawal, a rigorous evaluation of beneficial versus detrimental (phencyclidine-like) actions has not been done. The objective of the present investigation was to explore whether dizocilpine protects against ethanol withdrawal-induced increases in seizure susceptibility without being compromised by its phencyclidine-like behavioral actions. The effects of dizocilpine were assessed by using seizure threshold determinations and scoring of open field behaviors. Low dose dizocilpine administration preferentially protected against bicuculline seizure induction in ethanol-withdrawn female rats when compared with findings in ethanol-withdrawn male rats. In contrast, we found dramatic reductions in dizocilpine-induced open field behaviors during ethanol withdrawal in both male and female rats compared with findings for pair-fed control animals. [3H]MK-801 binding analysis ruled out changes in cerebral cortex or hippocampus receptor density or affinity as having a primary role in these differential responses. Taken together, our findings from these studies indicate that there are complex neuroadaptations in NMDA receptor systems after persistent ethanol exposure, manifested as either enhanced or reduced responses, depending on the measure used.

Topics: Animals; Brain; Dizocilpine Maleate; Ethanol; Female; Locomotion; Male; Rats; Rats, Sprague-Dawley; Seizures; Stereotyped Behavior; Substance Withdrawal Syndrome

Various transcriptional activators are induced in neurons concomitantly with long-lasting neural activity, whereas only a few transcription factors are known to act as neural activity-inducible transcription repressors. In this study, mRNA of DREAM (DRE-antagonizing modulator), a Ca(2+)-modulated transcriptional repressor, was demonstrated to accumulate in the mouse brain after pentylenetetrazol (PTZ)-induced seizures. Accumulation in the mouse hippocampus reached maximal level in the late phase (at 7-8 h) after PTZ injection. Kainic acid induced the same response. Interestingly, the late induction of DREAM expression required new protein synthesis and was blocked by MK801 suggesting that Ca(2+)-influx via NMDA receptors is necessary for the PTZ-mediated DREAM expression. In situ hybridization revealed that PTZ-induced DREAM mRNA accumulation was observed particularly in the dentate gyrus, cerebral cortex, and piriform cortex. The results of the present study demonstrate that DREAM is a neural activity-stimulated late gene and suggest its involvement in adaptation to long-lasting neuronal activity.

Topics: Animals; Calcium-Binding Proteins; Convulsants; Cycloheximide; Dizocilpine Maleate; Gene Expression Regulation; Hippocampus; In Situ Hybridization; Kainic Acid; Kv Channel-Interacting Proteins; Male; Mice; Neurons; Neuroprotective Agents; Pentylenetetrazole; Protein Synthesis Inhibitors; Repressor Proteins; RNA, Messenger; Seizures; Time Factors

The aim of the present work was to test in adult cats the capability of three glutamatergic agonists, NMDA, AMPA and ACDP as epileptogenic agents. Drugs were microinjected in amygdala or hippocampus, and once generated an epileptic focus three selective glutamatergic antagonists NMDA, CNQX and MCPG, were tested. Before and after injection both the EEG and the behavior were continuously monitored. The results were as follows: 1) AMPA showed a greater capability than NMDA or ACPD to generate a chronic epileptic focus; 2) AMPA elicited a greater epileptogenic effect in hippocampus than in amygdala; NMDA had similar epileptogenic effect in both cited structures, and ACPD had not effect; 3) of the three glutamatergic antagonists used to block a long lasting focus, the most effective one was CNQX, which showed a greater effect in hippocampus than in amygdala; 4) comparison between the epileptogenic effect of AMPA and kainic acid (first paper) in the same structure, showed that kainic acid is about 15 fold more epileptogenic. A discussion of the probable mechanisms of these results was undertaken.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Amygdala; Animals; Cats; Dizocilpine Maleate; Electrophysiology; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Hippocampus; Male; Microinjections; N-Methylaspartate; Neuroprotective Agents; Seizures

Application of 4-(aminomethyl)cyclohexanecarboxylic acid (tranexamic acid; TAMCA) to the central nervous system (CNS) has been shown to result in hyperexcitability and convulsions. However, the mechanisms underlying this action are unknown. In the present study, we demonstrate that TAMCA binds to the gamma-aminobutyric acid (GABA) binding site of GABA(A) receptors in membranes from rat cerebral cortex and does not interfere with N-methyl-D-aspartate receptors. Patch-clamp studies using human embryonic kidney cells transiently transfected with recombinant GABA(A) receptors composed of alpha 1 beta 2 gamma 2 subunits showed that TAMCA did not activate these receptors but dose dependently blocked GABA-induced chloride ion flux with an IC(50) of 7.1 +/- 3.1 mM. Application of TAMCA to the lumbar spinal cord of rats resulted in dose-dependent hyperexcitability, which was completely blocked by coapplication of the GABA(A) receptor agonist muscimol. These results indicate that TAMCA may induce hyperexcitability by blocking GABA-driven inhibition of the CNS.

Topics: Animals; Antifibrinolytic Agents; Binding, Competitive; Brain Chemistry; Cell Line; Dizocilpine Maleate; Dose-Response Relationship, Drug; GABA Agonists; GABA Antagonists; GABA-A Receptor Antagonists; Hindlimb; Humans; Male; Membrane Potentials; Membranes; Muscimol; Patch-Clamp Techniques; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Spinal Cord; Tranexamic Acid

The purpose of this study was to clarify the in vitro pharmacological profile and the in vivo activity of (3S)-7-chloro-3-[2-((1R)-1-carboxyethoxy)-4-aminomethylphenyl]aminocarbonylmethyl-1,3,4,5-tetrahydrobenz[c,d]indole-2-carboxylic acid hydrochloride (SM-31900). SM-31900 inhibited the binding of [3H]glycine and [3H]5,7-dichlorokynurenic acid, radioligands for the N-methyl-D-aspartate (NMDA) receptor glycine-binding site, to rat brain membranes in a competitive manner, with K(i) values of 11+/-2 and 1.0+/-0.1 nM, respectively, and completely prevented the binding of [3H]dizocilpine (MK-801), a radioligand for the NMDA receptor channel site. In cultures of rat cortical neurons, SM-31900 markedly prevented the neuronal cell death induced by transient exposure to glutamate, in a concentration-dependent manner. Its neuroprotective potency was much stronger than those of other glycine-binding site antagonists (4-trans-2-carboxy-5,7-dichloro-4-phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline (L-689,560), 5,7-dichlorokynurenic acid, and 7-chlorokynurenic acid). Furthermore, SM-31900 showed anticonvulsant activity when administered systemically, unlike other antagonists. These data indicate that SM-31900 is a systemically active antagonist with high affinity for the NMDA receptor glycine-binding site.

Topics: Aminoquinolines; Animals; Binding, Competitive; Brain; Cells, Cultured; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Fetus; Glutamic Acid; Indoles; Kynurenic Acid; Male; Neurons; Neuroprotective Agents; Neurotoxins; Radioligand Assay; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Seizures

To clarify the role of nitric oxide (NO) in the pathogenesis of seizures in susceptible EL mice, we investigated effects of three drugs potentially related to NO production, MK-801, dantrolene, and FK506, on convulsive seizures and brain NO metabolites (NOx). MK-801 or dantrolene, but not FK506, suppressed convulsive seizures in EL mice; only MK-801 reduced NOx in the brain. Our results suggested involvement of the N-methyl-D-aspartate receptor-channel complex and intracellular calcium mobilization, but not calcineurin, in the convulsions of EL mice.

Topics: Animals; Brain; Brain Chemistry; Calcineurin; Calcium; Dantrolene; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Immunosuppressive Agents; Injections, Intraperitoneal; Mice; Mice, Inbred Strains; Muscle Relaxants, Central; Nitrates; Nitric Oxide; Nitrites; Receptors, N-Methyl-D-Aspartate; Seizures; Tacrolimus

Both organophosphate (OP) and carbamate pesticides may produce seizures and death commonly attributed to the inhibition of acetylcholinesterase (AChE) and subsequent excess of acetylcholine (ACh). The anticonvulsant and neuroprotective properties of N-methyl-D-aspartate (NMDA) receptor antagonists in animals encouraged us to investigate their effects on the toxic and convulsant properties of OP and carbamate pesticides. Adult Swiss mice were systemically injected with the OP pesticide, chlorfenvinphos (CVP), or the carbamate pesticide, methomyl (MET). Both CVP and MET induced dose-dependent seizure activity and death in mice. Pretreatment with the muscarinic antagonist, atropine (ATR), at a dose of 1.8 mg/kg did not prevent seizures but decreased the lethal effects of CVP and MET. Pretreatment with the NMDA antagonists, dizocilpine (MK-801) at a dose of 1 mg/kg or 3-((R,S)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) at a dose of 10 mg/kg, influenced neither MET-induced seizures nor CVP- or MET-induced death. However, both MK-801 and CPP blocked CVP-induced seizures. Concurrent administration of ATR and the NMDA antagonists prevented seizures produced by CVP, but not those produced by MET. Nevertheless, both MK801 and CPP coadministered with ATR markedly enhanced its antilethal effects in CVP- and MET-intoxicated mice. The antidotes had no influence upon brain AChE activities in mice treated with saline or CVP or MET. It seems that combined treatment with ATR and NMDA receptor antagonists might be of clinical relevance.

Topics: Acetylcholinesterase; Animals; Atropine; Brain; Chlorfenvinphos; Cholinesterase Inhibitors; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Antagonism; Excitatory Amino Acid Antagonists; Lethal Dose 50; Male; Methomyl; Mice; Muscarinic Antagonists; Piperazines; Seizures

Glufosinate ammonium, a broad-spectrum herbicide, causes convulsion in rodents and humans. Because of the structural similarities between glufosinate and glutamate, the convulsion induced by glufosinate ammonium may be ascribed to glutamate receptor activation. Three N-methyl-D-asparate (NMDA) receptor antagonists, dizocilpine, LY235959, and Compound 40, and an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonist, NBQX, were coadministrated with glufosinate ammonium (80 mg/kg, intraperitoneally) in mice. Statistical analyses showed that the NMDA receptor antagonists markedly inhibited the convulsions, while the AMPA/kainate receptor antagonist had no effect on the convulsion. These results suggest that the convulsion caused by glufosinate ammonium is mediated through NMDA receptors.

Topics: Aminobutyrates; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Herbicides; Male; Mice; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Seizures

It has been shown that NMDA antagonists block the tonic but not the clonic component of seizures when they are injected in the oral region of the rat pontine reticular formation (PRF). The participation of the caudal PRF in the effects of NMDA antagonists upon the tonic and the clonic components of generalized seizures induced by pentylenetetrazol (PTZ) is unknown. The aim of the present study was to evaluate the effects of unilateral microinjections of competitive and non-competitive NMDA antagonists, 2-amino-7-phosphonoheptanoic acid (AP-7) and dizocilpine (MK-801), respectively, into the nucleus reticularis pontis caudalis of the rat PRF upon seizures induced by PTZ (70 mg/kg i.p.). MK-801 induced a dose-related decrease both in the incidence of generalized tonic-clonic seizures (GTCS) and in the presence of spikes in the EEG. MK-801 also increased GTCS latency. On the contrary, AP-7 did not have effects on GTCS. Interestingly, it induced ipsilateral circling behavior. These results suggest that in the caudal region of the rat PRF only non-competitive NMDA antagonists should block the generation of tonic and clonic components of generalized seizures.

Topics: 2-Amino-5-phosphonovalerate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Dizocilpine Maleate; Electroencephalography; Excitatory Amino Acid Antagonists; Male; Microinjections; N-Methylaspartate; Pentylenetetrazole; Pons; Rats; Rats, Wistar; Reticular Formation; Seizures

This study focused on the effects of status epilepticus on the activity of calcineurin, a neuronally enriched, calcium-dependent phosphatase. Calcineurin is an important modulator of many neuronal processes, including learning and memory, induction of apoptosis, receptor function and neuronal excitability. Therefore, a status epilepticus-induced alteration of the activity of this important phosphatase would have significant physiological implications. Status epilepticus was induced by pilocarpine injection and allowed to continue for 60 min. Brain region homogenates were then assayed for calcineurin activity by dephosphorylation of p-nitrophenol phosphate. A significant status epilepticus-dependent increase in both basal and Mn(2+)-dependent calcineurin activity was observed in homogenates isolated from the cortex and hippocampus, but not the cerebellum. This increase was resistant to 150 nM okadaic acid, but sensitive to 50 microM okadaic acid. The increase in basal activity was also resistant to 100 microM sodium orthovanadate. Both maximal dephosphorylation rate and substrate affinity were increased following status epilepticus. However, the increase in calcineurin activity was not found to be due to an increase in calcineurin enzyme levels. Finally, increase in calcineurin activity was found to be NMDA-receptor activation dependent. The data demonstrate that status epilepticus resulted in a significant increase in both basal and maximal calcineurin activity.

Topics: Animals; Brain; Calcineurin; Cerebral Cortex; Disease Models, Animal; Dizocilpine Maleate; Hippocampus; Kinetics; Male; Nitrophenols; Organ Specificity; Organophosphorus Compounds; Pilocarpine; Protein Tyrosine Phosphatases; Rats; Rats, Sprague-Dawley; Seizures; Status Epilepticus; Substrate Specificity

This study characterized the neuroprotective and behavioral effects of (3aS,6aS)-6a-naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-on (BAY 36-7620), a novel, selective and systemically active metabotropic glutamate (mGlu)(1) receptor antagonist. In the rat, neuroprotective effects were obtained in the acute subdural hematoma model (efficacy of 40-50% at 0.01 and 0.03 mg/kg/h, i.v. infusion during the 4 h following surgery); whereas in the middle cerebral artery occlusion model, a trend for a neuroprotective effect was obtained after triple i.v. bolus application of 0.03-3 mg/kg, given immediately, 2 and 4 h after occlusion. Hypothermic effects were mild and only obtained at doses which were considerably higher than those at which maximal neuroprotective efficacy was obtained, indicating that the neuroprotective effects are not a consequence of hypothermia. BAY 36-7620 protected against pentylenetetrazole-induced convulsions in the mouse (MED: 10 mg/kg, i.v.). As assessed in rats, BAY 36-7620 was devoid of the typical side-effects of the ionotropic glutamate (iGlu) receptor antagonists phencyclidine and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801). Thus, BAY 36-7620 did not disrupt sensorimotor gating, induce phencyclidine-like discriminative effects or stereotypical behavior, or facilitate intracranial self-stimulation behavior. Although behavioral stereotypies and disruption of sensorimotor gating induced by amphetamine or apomorphine were not affected by BAY 36-7620, the compound attenuated some behavioral effects of iGlu receptor antagonists, such as excessive grooming or licking, and their facilitation of intracranial self-stimulation behavior. It is concluded that mGlu(1) receptor antagonism results in neuroprotective and anticonvulsive effects in the absence of the typical side-effects resulting from antagonism of iGlu receptors.

Topics: Animals; Anticonvulsants; Behavior, Animal; Body Temperature; Brain Ischemia; Cerebral Cortex; Discrimination, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Exploratory Behavior; Infarction, Middle Cerebral Artery; Male; Mice; Naphthalenes; Neural Inhibition; Neuroprotective Agents; Phencyclidine; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Metabotropic Glutamate; Reflex, Startle; Seizures; Self Stimulation; Stereotyped Behavior

In this study, we evaluated whether beta-adrenoceptor antagonists may modify the protective efficacy of dizocilpine (MK-801), a NMDA receptor antagonist, and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), a non-NMDA (AMPA/kainate) receptor antagonist, against maximal electroshock-induced seizures in mice. Propranolol, acebutolol, metoprolol and atenolol were used in doses that did not alter the electroconvulsive threshold. Propranolol potentiated the anticonvulsant activity of MK-801 and GYKI 52466, significantly lowering their ED(50) values from 0.38 and 15.0 to 0.15 (P<0.001) and 8.4 mg/kg (P<0.001), respectively. Similarly, metoprolol lowered the ED(50) of MK-801 and GYKI 52466 from 0.38 and 15.0 to 0.17 (P<0.05) and 11.2 mg/kg (P<0.05). Acebutolol enhanced the protective action of GYKI 52466, lowering its ED(50) value from 15.0 to 12.2 mg/kg (P<0.05), but not that of MK-801. Atenolol, not penetrating the blood-brain barrier, did not affect the anticonvulsive efficacy of MK-801 and GYKI 52466. In conclusion, beta-adrenoceptor antagonists may act synergistically with excitatory amino acid receptor antagonists to inhibit generalised tonic-clonic seizures.

Topics: Adrenergic beta-Antagonists; Animals; Anti-Anxiety Agents; Anticonvulsants; Benzodiazepines; Disease Models, Animal; Dizocilpine Maleate; Drug Synergism; Electroshock; Excitatory Amino Acid Antagonists; Male; Mice; Motor Activity; Receptors, Glutamate; Seizures

The purification, characterization, and synthesis of conantokin-R (Con-R), an N-methyl-D-aspartate (NMDA) receptor peptide antagonist from the venom of Conus radiatus, are described. With the use of well defined animal seizure models, Con-R was found to possess an anticonvulsant profile superior to that of ifenprodil and dizocilpine (MK-801). With voltage-clamp recording of Xenopus oocytes expressing heteromeric NMDA receptors from cloned NR1 and NR2 subunit RNAs, Con-R exhibited the following order of preference for NR2 subunits: NR2B approximately NR2A > NR2C >> NR2D. Con-R was without effect on oocytes expressing the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluR1 or the kainate receptor subunit GluR6. In mouse cortical neurons voltage-clamped at -60 mV, Con-R application produced a slowly developing block of inward currents evoked by 10 microM NMDA and 1 microM glycine (IC(50) = 350 nM). At 3 microM, Con-R did not affect gamma-aminobutyric acid- or kainate-evoked currents. Con-R prevented sound-induced tonic extension seizures in the Frings audiogenic seizure-susceptible mice at i.c.v. doses below toxic levels. It was also effective at nontoxic doses in CF#1 mice against tonic extension seizures induced by threshold (15 mA) and maximal (50 mA) stimulation, and it partially blocked clonic seizures induced by s.c. pentylenetetrazol. In contrast, MK-801 and ifenprodil were effective only at doses approaching (audiogenic seizures) or exceeding (electrical and pentylenetetrazol seizures) those required to produce significant behavioral impairment. These results indicate that the subtype selectivity and other properties of Con-R afford a distinct advantage over the noncompetitive NMDA antagonists MK-801 and ifenprodil. Con-R is a useful new pharmacological agent for differentiation between the anticonvulsant and toxic effects of NMDA antagonists.

Topics: Animals; Anticonvulsants; Behavior, Animal; Binding, Competitive; Cerebral Cortex; Conotoxins; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Evoked Potentials; Female; gamma-Aminobutyric Acid; Glutamic Acid; In Vitro Techniques; Kainic Acid; Male; Mice; Mollusk Venoms; Oocytes; Pentylenetetrazole; Piperidines; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Seizures; Sound; Xenopus

Severe temporal lobe epilepsy in humans is often associated with loss of neurons in the hippocampus and memory deficits. In Experiment 1, 60 min of continuous electrical stimulation of the perforant path sufficient to produce seizures resembling status epilepticus and loss of hilar and pyramidal cells in the hippocampus, produced a deficit in spatial mapping in the Morris water tank. In particular, the previously stimulated rats took longer and swam farther to find a hidden, but not a visually cued, platform, and, in contrast to the unstimulated control rats, were not disrupted by movement of the platform to a new location. In Experiment 2, a single injection of the non-competitive NMDA receptor antagonist, MK-801 (1.0 mg/kg), just prior to the perforant path stimulation reduced the seizures, hippocampal neuronal loss, and deficit in spatial mapping. These data suggest that temporal lobe seizures can induce deficits in spatial memory by selectively destroying neurons within the hippocampus, and that the mechanism by which this occurs involves the activation of NMDA receptors, and, perhaps, consequent excitotoxicity.

Topics: Animals; Brain Mapping; Dizocilpine Maleate; Electric Stimulation; Escape Reaction; Excitatory Amino Acid Antagonists; Hippocampus; Male; Maze Learning; Mental Recall; Neurons; Orientation; Perforant Pathway; Rats; Rats, Sprague-Dawley; Seizures

Bilateral intracerebroventricular infusion of dl-homocysteic acid (DL-HCA) (600 nmol on each side) to immature 12-day-old rats induced generalized clonic-tonic seizures, recurring frequently for at least 90 min, with a high rate of survival. Electrographic recordings from sensorimotor cortex, hippocampus, and striatum demonstrated isolated spikes in the hippocampus and/or striatum as the first sign of dl-HCA action. Generalization of epileptic activity occurred during generalized clonic-tonic seizures, but electroclinical correlation was very low; dissociation between EEG pattern and motor phenomena was common. Seizures were accompanied by large decreases of cortical glucose and glycogen and by approximately 7- to 10-fold accumulation of lactate. ATP and phosphocreatine (PCr) levels remained unchanged even during longlasting (3 h) convulsions. Metabolite levels became normalized during the recovery period (24 h). The examination of the effect of selected antagonists of NMDA [AP7 (18.5 and 37 mg/kg, respectively), MK-801 (0.5 mg/kg)] and non-NMDA [NBQX (10, 15 and 30 mg/kg, respectively)] receptors revealed that seizures could be attenuated or prevented (depending on the dose employed) by antagonists of both NMDA and non-NMDA receptors, as evaluated not only according to the suppression of behavioral manifestations of seizures, but also in terms of the protection of metabolite changes accompanying seizures. All antagonists employed, when given alone in the same doses as those used for seizure protection, did not influence metabolite levels, with the exception of increased glucose concentrations. Furthermore, the pronounced anticonvulsant effect could be achieved by the combined treatment with low subthreshold doses of NMDA (AP7) and non-NMDA (NBQX) receptor antagonists, which may be of potential significance for a new approach to the treatment of epilepsy.

Topics: 2-Amino-5-phosphonovalerate; Age Factors; Animals; Cerebral Cortex; Disease Models, Animal; Dizocilpine Maleate; Electroencephalography; Energy Metabolism; Epilepsy; Excitatory Amino Acid Antagonists; Glucose; Homocysteine; Injections, Intraventricular; Male; Neuroprotective Agents; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

Our previous studies have shown a local decrease in glutamate and aspartate levels during seizures, induced by picrotoxin microdialysis in the hippocampus of chronic freely moving rats. In this paper, we study the effect of continuous hippocampal microperfusion of the NMDA, AMPA and kainate glutamate receptor inhibitors 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (MK-801); 6,7-dinitroquinoxaline-2,3-dione (DNQX), and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466). We also examine the action of L(-)-threo-3-hydroxyaspartic acid (THA), a glutamate and aspartate reuptake blocker, on the modification of extracellular glutamate and aspartate levels induced by picrotoxin, using the microdialysis method in freely moving rats. We found that changes in extracellular hippocampal concentrations in both amino acids are prevented by NMDA, AMPA and kainate receptor inhibitors. Seizures elicited under DNQX also induce a transient increase in aspartate extracellular levels coincident with seizure time. L(-)-threo-3-hydroxyaspartic acid increased the basal extracellular concentrations of both amino acids, but did not prevent the seizure-related decrease. Our results suggest that glutamate, the major neurotransmitter at the synaptic level, may also play an important role in non-synaptic transmission during seizures.

Topics: Animals; Anti-Anxiety Agents; Aspartic Acid; Benzodiazepines; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Extracellular Space; Glutamic Acid; Hippocampus; Male; Microdialysis; Picrotoxin; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Seizures

Prolonged seizures (status epilepticus) induced by kainic acid activate programmed cell death mechanisms, and it is believed that kainic acid-induced status epilepticus induces neuronal apoptosis. In order to test this hypothesis, adult rats were subjected to 3-h kainic acid-induced seizures, with 24- or 72-h recovery periods. Neuronal death was assessed by light microscopy with the Hematoxylin and Eosin stain and with in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL stain), by electron microscopy, and by agarose gel electrophoresis of DNA extracted from five vulnerable brain regions. Spontaneous and MK-801-induced apoptotic neurons from retrosplenial cortex of neonatal rats, evaluated by light and electron microscopy, were used as positive controls for apoptosis. Surprisingly, the large chromatin clumps of apoptotic neurons were TUNEL negative, whereas the cytoplasm showed light-to-moderate TUNEL staining, consistent with a lack of identifiable nuclear membranes ultrastructurally, and with intermingling of nuclear and cytoplasmic contents. Ultrastructurally, the acidophilic neurons produced by kainic acid-induced status epilepticus, identified with Hematoxylin and Eosin stain, were dark, shrunken and necrotic, with pyknotic nuclei containing small, dispersed chromatin clumps, and with cytoplasmic vacuoles, some of which were swollen, disrupted mitochondria. No apoptotic cells were seen. Acidophilic neurons were found in up to 20 of 23 brain regions examined and comprised 10-25% of the total number of neurons examined. A subset of these neurons (<10% of the total number of neurons in five of 23 regions) had TUNEL-positive nuclei 72h but not 24h after status epilepticus. Internucleosomal DNA cleavage (DNA "laddering") occurred in the four most damaged brain regions examined by electron microscopy 24h after SE and the three most damaged regions 72h after status epilepticus. Our results demonstrate that kainic acid-induced status epilepticus produces neuronal necrosis and not apoptosis in adult rats. The necrotic neurons show nuclear pyknosis, chromatin condensation and DNA laddering. Programmed cell death mechanisms activated by kainic acid-induced status epilepticus occur in neurons which become necrotic and could contribute to necrotic, as well as apoptotic, neuronal death.

Topics: Animals; Apoptosis; Dizocilpine Maleate; DNA Fragmentation; Entorhinal Cortex; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Hippocampus; In Situ Nick-End Labeling; Kainic Acid; Male; Microscopy, Electron; Necrosis; Neurons; Nucleosomes; Rats; Rats, Wistar; Seizures; Status Epilepticus

We examined the effects of kainic acid (KA)-induced seizure on the expression of the pituitary adenylate cyclase-activating polypeptide (PACAP) gene in the paraventricular nucleus (PVN) of rats using in situ hybridization histochemistry. Subcutaneous administration of KA (12 mg/kg) in adult male Sprague-Dawley rats caused a progressive development of seizure behavior. An induction of the PACAP gene expression in the medial parvocellular part of the PVN (mpPVN) was observed 3, 6, 12, 24 and 48 h after subcutaneous administration of KA. From a nearly undetectable level, PACAP gene expression increased in the mpPVN and reached maximum 12 h after subcutaneous administration of KA. PACAP gene expression returned to near basal level 48 h after stimulation with KA. Using a specific monoclonal PACAP antibody, PACAP immunoreactivity (-IR) gradually increased during the following 24 h after KA administration. In controls, PACAP-IR was located exclusively in nerve fibers of the mpPVN, whereas KA administration induced PACAP-IR in cell bodies of the mpPVN, and a dense accumulation of PACAP-IR nerve fibers in the external zone of the median eminence was observed. Induction of the PACAP gene expression following KA-induced seizure was significantly reduced by pretreatment with diazepam or MK-801 (nonselective N-methly-D-aspartate receptor antagonist). These results suggest that PACAP in the hypothalamo-adenohypophysial system may have a hypophysiotropic role during KA-induced seizure.

Topics: Animals; Anticonvulsants; Diazepam; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Immunohistochemistry; Kainic Acid; Male; Neuropeptides; Paraventricular Hypothalamic Nucleus; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures

The role of glutamate receptors in the inferior colliculus (IC) in audiogenic and audiogenic-like seizures was investigated in adult rats with transient neonatal hypothyroidism by 0.02% propylthiouracil (PTU) treatment through mother's milk (PTU rats) and in naive rats treated intracisternally with N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA), or cyclothiazide, an inhibitor of rapid AMPA receptor desensitization. All rats showed audiogenic or audiogenic-like seizures characterized by running fit (RF) and generalized tonic-clonic seizures (GTCS). While systemically administered MK-801 inhibited GTCS, intracisternally administered NBQX inhibited RF and GTCS in both audiogenic and audiogenic-like seizures. Auditory stimulation shortened the latency to GTCS induced by AMPA, but not NMDA, at a subclinical dose and further elongated the shortened duration of RF, but not GTCS, induced by MK-801 pretreatment. Furthermore, Northern blot analysis was used to evaluate the expression of the immediate-early gene c-fos in the IC following induction of audiogenic or audiogenic-like seizures. The significant induction of c-fos mRNA by audiogenic seizures in PTU rats or by AMPA- or cyclothiazide-induced seizures in naive rats was prominent in the IC. MK-801 suppressed c-fos mRNA expression in the IC induced by audiogenic seizures in PTU rats or by AMPA-induced seizures in naive rats. NBQX suppressed the expression of c-fos mRNA in the IC induced by AMPA-induced seizures but did not suppress c-fos mRNA in PTU rats or rats with cyclothiazide-induced seizures. Auditory stimuli failed to affect c-fos mRNA induction by AMPA. The present study suggests that audiogenic-like seizures can be reproduced by glutamate receptor agonists in which AMPA receptors are primarily linked to the initiation of audiogenic seizures (RF) while NMDA receptors presumably located within the IC are involved in the propagation of GTCS in audiogenic seizures.

Topics: Acoustic Stimulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Animals, Suckling; Benzothiadiazines; Dizocilpine Maleate; Drug Administration Routes; Excitatory Amino Acid Antagonists; Female; Hypothyroidism; Inferior Colliculi; Injections, Intraventricular; Male; Maternal Exposure; N-Methylaspartate; Propylthiouracil; Proto-Oncogene Proteins c-fos; Quinoxalines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Seizures

The development of symptomatic epilepsy is a model of long-term plasticity changes in the central nervous system. The rat pilocarpine model of epilepsy was utilized to study persistent alterations in calcium/calmodulin-dependent kinase II (CaM kinase II) activity associated with epileptogenesis. CaM kinase II-dependent substrate phosphorylation and autophosphorylation were significantly inhibited for up to 6 weeks following epileptogenesis in both the cortex and hippocampus, but not in the cerebellum. The net decrease in CaM kinase II autophosphorylation and substrate phosphorylation was shown to be due to decreased kinase activity and not due to increased phosphatase activity. The inhibition in CaM kinase II activity and the development of epilepsy were blocked by pretreating seizure rats with MK-801 indicating that the long-lasting decrease in CaM kinase II activity was dependent on N-methyl-D-aspartate receptor activation. In addition, the inhibition of CaM kinase II activity was associated in time and regional localization with the development of spontaneous recurrent seizure activity. The decrease in enzyme activity was not attributed to a decrease in the alpha or beta kinase subunit protein expression level. Thus, the significant inhibition of the enzyme occurred without changes in kinase protein expression, suggesting a long-lasting, post-translational modification of the enzyme. This is the first published report of a persistent, post-translational alteration of CaM kinase II activity in a model of epilepsy characterized by spontaneous recurrent seizure activity.

Topics: Animals; Brain; Calcium-Calmodulin-Dependent Protein Kinases; Dizocilpine Maleate; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Intercellular Signaling Peptides and Proteins; Isoenzymes; Male; Okadaic Acid; Peptides; Phosphoric Monoester Hydrolases; Phosphorylation; Pilocarpine; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Secondary Prevention; Seizures; Status Epilepticus; Time Factors

We previously created a transgenic mouse model of comorbid Tourette's syndrome and obsessive-compulsive disorder (TS+OCD), by expressing a neuropotentiating cholera toxin (CT) transgene in a subset of dopamine D1 receptor-expressing (D1+) neurons thought to induce cortical and amygdalar glutamate output. To test glutamate's role in the TS+OCD-like disorder of these transgenic mice (D1CT-7 line), the effects of glutamate receptor-binding drugs on their behavior were examined. MK-801, a non-competitive NMDA receptor antagonist that indirectly stimulates cortical-limbic glutamate output, aggravated a transgene-dependent abnormal behavior (repetitive climbing and leaping) in the D1CT-7 mice at doses insufficient to induce stereotypies, and more readily induced stereotypies and limbic seizure behaviors at high doses. NBQX, a seizure-inhibiting AMPA receptor antagonist, reduced only the MK-801-dependent stereotypic and limbic seizure behavior of D1CT-7 mice, but not their transgene-dependent behaviors. These data imply that TS+OCD-like behavior is mediated by cortical-limbic glutamate, but that AMPA glutamate receptors are not an essential part of this behavioral circuit. Our findings lead to the prediction that the symptoms of human Tourette's syndrome and obsessive-compulsive disorder are elicited by excessive forebrain glutamate output.

Topics: Animals; Cerebral Cortex; Comorbidity; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Limbic System; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Motor Activity; Obsessive-Compulsive Disorder; Quinoxalines; Seizures; Tourette Syndrome

Rab GDP dissociation inhibitor alpha (Rab GDIalpha) is a regulator of the Rab small G proteins implicated in neurotransmission, and mutations of Rab GDIalpha cause human X-linked mental retardation associated with epileptic seizures. In Rab GDIalpha-deficient mice, synaptic potentials in the CA1 region of the hippocampus displayed larger enhancement during repetitive stimulation, which was apparently opposite to the phenotype of Rab3A-deficient mice. Furthermore, the Rab GDIalpha-deficient mice showed hypersensitivity to bicuculline, an inducer of epileptic seizures. These results suggest that Rab GDIalpha plays a specialized role in Rab3A recycling to suppress hyperexcitability via modulation of presynaptic forms of plasticity.

Topics: Animals; Base Sequence; Dizocilpine Maleate; DNA Primers; Excitatory Amino Acid Antagonists; GABA Antagonists; Guanine Nucleotide Dissociation Inhibitors; Hippocampus; Humans; In Vitro Techniques; Mice; Mice, Inbred C57BL; N-Methylaspartate; Neuronal Plasticity; rab3 GTP-Binding Proteins; Seizures; Subcellular Fractions; Synaptic Transmission

The aim of the study was to examine the role of NMDA receptors in modulation of protective effect against bicuculline toxicity after transient brain ischemia in mice. Animals were exposed for 30 min to bilateral clamping of the common carotid arteries (BCCA) in anaesthesia. MK-801 was administered intraperitoneally in two paradigms: a) acute treatment: twice, 1.0 mg/kg; 1 hour before clamping and 6 hours after re-circulation and b) chronic treatment: 0.1 mg/kg; started 24 hours after re-circulation and continued once daily for 13 days, the last injection was administered 24 hours before seizure induction. 14 days after BCCA, the animals were injected with bicuculline (3.5 mg/kg s.c). A significant decrease in seizure susceptibility could be observed in BCCA treated mice compared with sham-operated controls. Acute treatment with MK-801 did not affect seizure activity both in sham and BCCA mice. Chronic treatment with the drug potentiated anticonvulsant effect of brain ischemia but had no influence on seizure activity in sham-operated mice. The analysis of GABA content in brain tissue performed 14 days after BCCA showed a moderate increase in vehicle-treated mice and significant elevation after chronic treatment with MK-801. It can be suggested that NMDA receptors are not involved in the induction of a protective effect against bicuculline toxicity after transient brain ischemia. The prolonged treatment with low doses of MK-801 may potentiate a developed process in a mechanism of chemical preconditioning.

Topics: Age Factors; Animals; Behavior, Animal; Bicuculline; Brain Chemistry; Convulsants; Dizocilpine Maleate; Epilepsy; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Ischemic Attack, Transient; Ischemic Preconditioning; Male; Mice; Receptors, N-Methyl-D-Aspartate; Seizures; Survival Rate

The aim of this study was to evaluate the contribution of ionotropic glutamate receptors to kindled seizure-evoked somatostatin release in the hippocampus, using a microdialysis approach. Basal and amygdala stimulation-evoked somatostatin-like immunoreactivity (-LI) release was significantly greater in kindled compared to naive rats. In naive rats, neither hippocampal perfusion with the selective AMPA/kainate receptor antagonist GYKI 52466 nor with the selective NMDA receptor antagonist MK-801 affected behavior, EEG, or somatostatin-LI release. In kindled rats, GYKI 52466 was still devoid of any effect, while MK-801 significantly decreased stimulus-evoked (but not basal) somatostatin-LI efflux. MK-801 produced identical effects when injected i.p. This study provides the first direct evidence that kindled seizure-evoked somatostatin release in the hippocampus is partly NMDA receptor dependent.

Topics: Amygdala; Animals; Disease Models, Animal; Dizocilpine Maleate; Electric Stimulation; Epilepsy; Excitatory Amino Acid Antagonists; Glutamic Acid; Hippocampus; Kindling, Neurologic; Male; Neurons; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Seizures; Somatostatin

Ibogaine, a putative antiaddictive drug, is remarkable in its apparent ability to downgrade withdrawal symptoms and drug craving for extended periods of time after a single dose. Ibogaine acts as a non-competitive NMDA receptor antagonist, while NMDA has been implicated in long lasting changes in neuronal function and in the physiological basis of drug addiction. The purpose of this study was to verify if persistent changes in NMDA receptors could be shown in vivo and in vitro after a single administration of ibogaine. The time course of ibogaine effects were examined on NMDA-induced seizures and [3H] MK-801 binding to cortical membranes in mice 30 min, 24, 48, and 72 h post treatment. Ibogaine (80 mg/kg, ip) was effective in inhibiting convulsions induced by NMDA at 24 and 72 hours post administration. Likewise, [3H] MK-801 binding was significantly decreased at 24 and 72 h post ibogaine. No significant differences from controls were found at 30 min or 48 h post ibogaine. This long lasting and complex pattern of modulation of NMDA receptors prompted by a single dose of ibogaine may be associated to its antiaddictive properties.

Topics: Animals; Cell Membrane; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Ibogaine; Male; Mice; Motor Activity; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Seizures

The stereoselective synthesis and biological activity of NPS 1407 (4a), (S)-(-)-3-amino-1,1-bis(3-fluorophenyl)butane, a potent, stereoselective antagonist of the NMDA receptor, are described. The racemate (4) was found to be active at the NMDA receptor in an in vitro assay, prompting the synthesis of the individual stereoisomers. The S isomer (4a) was found to be 12 times more potent than the R isomer (4b). Compound 4a demonstrated in vivo pharmacological activity in neuroprotection and anticonvulsant assays.

Topics: Animals; Anticonvulsants; Cerebellum; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Ischemic Attack, Transient; Mice; Molecular Structure; Neuroprotective Agents; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Stereoisomerism

2,3 dimercaptopropanol (BAL), is a dithiol chelating agent, used for the treatment of heavy metal intoxication; however, this compound has low therapeutic efficacy and in some situations may cause neurotoxic effects. In experimental models, administration of high doses of BAL produces seizures that culminate in animal death. However, investigations on the modulation of neurotransmitter system(s) involved in BAL-induced seizures are still lacking in the literature. In the present study, the neurotoxicity of BAL, as measured by the manifestation of seizures was examined and the modulation of glutamatergic and GABAergic receptors and ion channels potentially involved in BAL-induced seizures was investigated. The results demonstrated that BAL (18.6 mg/kg) induced seizures and all mice died within one day. GABAergic allosteric modulators (3 or 12 mg/kg diazepam and 50 mg/kg phenobarbital) blocked the appearance of seizure and reduced almost completely the death caused by BAL. Carbamazepine (5 mg/kg) significantly reduced the incidence of BAL-induced seizures, while sodium valproate and MK-801 were not effective in reducing the incidence of seizures. Valproate (300 mg/kg) and MK-801(0.5 mg/kg) prolonged the latencies for onset of seizures; however, all animals died within one day after BAL administration. High doses of ZnCl2 (135 mg/kg) blocked the appearance of seizures episodes, but no animal survived more than one day. The content of total non-protein -SH in brain of mice treated with 18.6 and 124 mg/kg BAL increased from 0.9+/-0.3 nmol/g (control animals) to 1.7+/-0.3 and 3.5+/-0.8 nmol/g, respectively. In vitro, 0.1-1 mM concentrations of BAL inhibited [3H]glutamate and [3H]MK-801 binding, but increased the binding of [3H]muscimol to brain synaptic plasma membrane. The results reported here demonstrate that GABAergic allosteric modulators (diazepam and phenobarbital) and carbamazepine, a compound that acts by prolonging the recovery of voltage-activated ion channels from inactivation, are able to abolish BAL-induced seizures, while the NMDA antagonist (MK-801) prolonged the latencies for onset of seizures suggesting that modulators of this subtype of glutamate receptor have a modest role on BAL-induced seizures. The results of the present study suggest that allosteric modulators of GABAergic system and carbamazepine, a voltage-gated Na+-channel antagonist, should be considered for the treatment of animals or patients intoxicated with BAL.

Topics: Animals; Anticonvulsants; Brain; Cell Membrane; Chelating Agents; Dimercaprol; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Mice; Neuroprotective Agents; Neurotoxins; Seizures; Sulfhydryl Compounds

Chronic in vivo models of epilepsy provide a suitable strategy for quantifying epileptogenesis, as well as investigating neurochemical changes associated with neuronal plasticity that leads to seizuring conditions. The aim of this paper was to investigate antiepileptogenic properties of phenobarbital, focusing on the neurochemical changes associated with repeated seizures induced by low convulsive dose of pentylenetetrazol (PTZ) (60 mg/kg, sc) in mice. Phenobarbital (10 and 30 mg/kg, ip) significantly diminished the severity of seizures induced by PTZ. Repeated PTZ administration was associated with an increase in [3H]glutamate binding (B(max) 196.6+/-10.2 pmol/mgxcontrol B(max) 137.7+/-17.0 pmol/mg). Regarding NMDA receptors, repeated PTZ administration was likewise associated with an increase in [3H]MK-801 binding (0.55+/-0.02 pmol/mgxcontrol 0.32+/-0.01 pmol/mg). In addition, phenobarbital (10 mg/kg) prevented the increase in [3H]glutamate binding (B(max) 133.7+/-11.4 pmol/mg), as well as in [3H]MK-801 binding (phenobarbital 10 and 30 mg/kg, 0.33+/-0.01 and 0.34+/-0.01 pmol/mg, respectively). This study reveals an interesting capability of phenobarbital in interfering with the establishment of both the behavioral expression and associated neurochemical changes induced by the repeated administration of low convulsive dose of PTZ, which may be important in the context of preventing epileptogenesis.

Topics: Animals; Anticonvulsants; Cerebral Cortex; Convulsants; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Mice; Pentylenetetrazole; Phenobarbital; Seizures

To characterize the potential interaction between the excitatory and inhibitory neurotransmitter systems, the effects of dizocilpine, CPP, and lorazepam on open-field behavior and pentylenetetrazol-induced seizures were evaluated in mice. Dizocilpine (0.01-0.1 mg/kg), CPP (1-10 mg/kg), or vehicle was administered intraperitoneally 15 min prior to lorazepam (0.2-2 mg/kg) or vehicle. Behavioral monitoring began 25 min after the lorazepam injection. Upon completion of testing, unrestrained mice were infused intravenously with pentylenetetrazole until the onset of a full tonic-clonic seizure. The highest dose of dizocilpine by itself significantly increased the average distance traveled, the number of rears, and the number of stereotypies during the test period. Lorazepam alone dose dependently decreased activity on all behavioral parameters. Lorazepam also completely antagonized the hyperactivity produced by dizocilpine when the two compounds were coadministered. This antagonism is most likely due to an interaction in the regulation of dopaminergic tone which underlies motor activity. Lorazepam exerted a dose-dependent anticonvulsant effect. Dizocilpine alone had no effect on seizure induction and did not potentiate the anticonvulsive effect of lorazepam when coadministered with lorazepam. CPP reduced the number of rears and the number of stereotypies during the test period. CPP did not alter the pentylenetetrazol-induced seizure threshold and did not influence the anticonvulsant effect of lorazepam.

Topics: Animals; Dizocilpine Maleate; Drug Antagonism; Excitatory Amino Acid Antagonists; GABA Modulators; Lorazepam; Male; Mice; Mice, Inbred ICR; Motor Activity; Pentylenetetrazole; Piperazines; Receptors, N-Methyl-D-Aspartate; Seizures; Stereotyped Behavior

The scorpion venom peptide toxins tityustoxin-K(alpha) (TsTx-K(alpha)) and pandinustoxin-K(alpha) (PiTx-K(alpha)) are novel, highly potent and selective blockers of voltage-activated K+ channels. PiTx-K(alpha) preferentially blocks rapidly inactivating (A-type) K+ channels whereas TsTx-K(alpha) is selective for slowly inactivating (delayed rectifier-type) channels. K+ channel blockers are known to induce seizures, but the specific K channel types that can serve as convulsant targets are not well defined. To address this issue, we examined for convulsant activity the K+ channel type-specific scorpion toxins and the selective K+ channel antagonists 4-aminopyridine (4-AP), an inhibitor of A-type voltage-activated K+ channels, and paxilline, a selective blocker of large conductance (maxi K) Ca(2+)-activated K+ channels. Intracerebroventricular injection of recombinant TsTx-K(alpha) and PiTx-K(alpha) in mice produced limbic and clonic-tonic seizures. The severity of the seizures increased during the 60-min period following injection, culminating in continuous clonic seizure activity (status epilepticus), tonic hindlimb extension, and eventually in death. The estimated doses producing limbic and clonic seizures in 50% of animals (CD50) for TsTx-K(alpha) and PiTx-K(alpha) were 9 and 33 ng, respectively. 4-AP produced seizure activity similar to the toxins (CD50, 76 ng) whereas paxilline failed to induce seizures at doses up to 13.5 microg. Carbamazepine protected fully against the toxin- and 4-AP-induced seizures whereas phenytoin had variable activity against the clonic component although it was protective against tonic hindlimb extension. The AMPA receptor antagonist GYKI 52466 also conferred full protection against toxin-induced seizures, but the NMDA receptor antagonists (R)-CPP and dizocilpine failed to affect limbic and clonic seizures, although they protected against hindlimb extension. We conclude that selective blockade of delayed rectifier- or A-type voltage-activated K+ channels can produce limbic, clonic and tonic seizures, whereas blockade of maxi K-type Ca(2+)-activated K+ channels does not. The convulsant effects may be related to enhanced glutamate release and, in the case of the limbic and clonic convulsions, activation of AMPA receptors.

Topics: 4-Aminopyridine; Animals; Anti-Anxiety Agents; Anticonvulsants; Benzodiazepines; Carbamazepine; Dizocilpine Maleate; Electroencephalography; Excitatory Amino Acid Antagonists; Injections, Intraventricular; Male; Mice; Neuroprotective Agents; Phenytoin; Potassium Channel Blockers; Scorpion Venoms; Seizures

In order to investigate the pharmacodynamic basis of the previously-established anticonvulsant properties of linalool, we examined the effects of this compound on behavioral and neurochemical aspects of glutamate expression in experimental seizure models. Specifically, linalool effects were investigated to determine its inhibition of (i) L-[3H]glutamate binding at CNS (central nervous system membranes), (ii) N-methyl-D-aspartate (NMDA)-induced convulsions, (iii) quinolinic acid (QUIN)-induced convulsions, and the behavioral and neurochemical correlates of PTZ-kindling. The data indicate that linalool modulates glutamate activation expression in vitro (competitive antagonism of L-[3H]glutamate binding) and in vivo (delayed NMDA convulsions and blockage of QUIN convulsions). Linalool partially inhibited and significantly delayed the behavioral expression of PTZ-kindling, but did not modify the PTZ-kindling-induced increase in L-[3H]glutamate binding.

Topics: Acyclic Monoterpenes; Animals; Anticonvulsants; Cerebral Cortex; Disease Models, Animal; Dizocilpine Maleate; Glutamic Acid; Kindling, Neurologic; Male; Monoterpenes; N-Methylaspartate; Pentylenetetrazole; Phenobarbital; Quinolinic Acid; Radioligand Assay; Rats; Rats, Wistar; Seizures; Terpenes

Glutamate NMDA receptor has been implicated in brain developmental processes as well as in excitotoxicity and seizure mediation. A previous study has shown that an acute episode of seizures for 30 min in rats altered NMDA receptor characteristics, mainly in the very immature animal. In order to assess whether receptor modifications may also account for long-lasting cerebral disabilities, medium- and long-term consequences of repeated seizures in developing rats on brain NMDA receptor properties were investigated. Seizures were induced once a day for 3 consecutive days, either from post-natal day 5 (P5) to P7 or from P15 to P17. NMDA receptors were then analysed at P15, P25 and P60 (adulthood) by measuring specific binding of [3H]MK-801 on brain membrane preparations. In addition, allosteric modulation of NMDA receptors by exogenous glutamate and glycine was investigated. Seizures from P5 to P7 led to a 22% increase in the density of [3H]MK-801 binding sites measured at P15, but did not affect NMDA receptor density or affinity at P25 or P60. P15-P17 seizures led to a 21% decrease in the density of binding sites and to a 33% decrease in receptor dissociation constant at P25, while they were without effect at P60. Moreover, P5-P7 and P15-P17 seizures were both associated with a suppression of the glutamate/glycine-induced receptor activation at P60. These modifications might account for long-term alterations in cerebral excitability or plasticity after early convulsive disorders, with regards to altered cognitive capacities, epileptogenesis and brain susceptibility to recurrent seizures.

Topics: Aging; Animals; Animals, Newborn; Binding Sites; Binding, Competitive; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Rats; Receptors, N-Methyl-D-Aspartate; Recurrence; Seizures; Time Factors

We have previously shown that NMDA receptor activation during status epilepticus (SE) is required to produce epilepsy in in vitro and in vivo models. As in human symptomatic epilepsy, the epilepsy in these models is permanent, suggesting that the pathological activation of NMDA receptors causes permanent plasticity changes in the brain. Ca(2+) influx through NMDA receptors is known to transiently activate a key transcription factor, serum response factor (SRF). Thus, we investigated whether this factor, in terms of its expression and ability to bind to the consensus serum response element, was altered long term in the pilocarpine model of epilepsy. In hippocampal nuclear extracts, SRF binding to DNA was significantly increased over saline-injected control rats at 24 hr and at 8 weeks after the onset of SE. This increase was shown to be the result of significantly elevated levels of SRF. DNA binding was also persistently increased in the cortical, but not in the cerebellar, extracts. Hippocampal expression of SRF was localized to neurons using immunohistochemistry. NMDA receptor activation during SE was required for these changes to take place, and the spontaneous seizures seen in epileptic rats did not appear to be responsible for the increase in SRF. The results demonstrate that SRF is persistently elevated after SE in the pilocarpine model of epilepsy and support the theory that long-term gene changes in this model occur and are associated with the long-lasting plasticity changes that are initiated during epileptogenesis.

Topics: Animals; Brain; Cell Nucleus; Cerebellum; Cerebral Cortex; Dizocilpine Maleate; DNA-Binding Proteins; Electroshock; Gene Expression Regulation; Hippocampus; Humans; Male; Neuronal Plasticity; Nuclear Proteins; Oligodeoxyribonucleotides; Organ Specificity; Phenytoin; Pilocarpine; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Serum Response Factor; Status Epilepticus; Transcription Factors

Organophosphate poisoning is associated with adverse effects on the central nervous system such as seizure/convulsive activity and long term changes in neuronal networks. This study reports on investigations designed to assess the consequences of soman exposure on excitatory amino acids receptors in the rat brain. In addition, the protective effects of caramiphen which acts at these receptors, and scopolamine, which does not, was determined on soman-induced alteration in rat brain functions. Administration of soman (1xLD50) to pyridostigmine pretreated rats produced seizure activity (measured by EEG monitoring) in all animals tested. Estimation of [3H]MK-801 binding to brain membranes from intoxicated rats revealed a marked decrease in Bmax value 24 but not 2 hrs following soman administration. The specific nature of these effects of soman was demonstrated by the findings that [3H]flunitrazepam binding to central benzodiazepine receptors remained unchanged in soman-poisoned rat brain membranes. Both scopolamine and caramiphen, when used prophylactically prevented the lethal effect of soman and completely blocked the development of electrographic seizure activity (EGSA). In contrast, only caramiphen abolished soman-induced modifications in NMDA/ion channel characteristics. Caramiphen displaced [3H]MK-801 bound to the NMDA/ion channel complex, possibly by interacting with the Zn2+ site whereas scopolamine did not. Moreover, caramiphen, but not scopolamine, partially protected mice from NMDA-induced lethality. Thus, it is suggested that an important component of the protective efficacy of caramiphen against organophosphate poisoning might be attributed to its ability to modulate NMDA receptors in addition to its anticholinergic properties.

Topics: Animals; Brain; Cholinesterase Inhibitors; Cyclopentanes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Electroencephalography; Excitatory Amino Acid Antagonists; Flunitrazepam; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Parasympatholytics; Protein Binding; Pyridostigmine Bromide; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Scopolamine; Seizures; Soman; Time Factors

In this study, we examined the acute anticonvulsant spectrum of (1) dizocilpine (0.03-3 mg/kg), CGS 19755 (1-10 mg/kg), and 7-chlorokynurenic acid (1-100 nmol) (NMDA receptor/ionophore complex antagonists); (2) muscimol (0.1-10 nmol; direct GABA(A) agonist); (3) YM90K (3-10 mg/kg; AMPA receptor antagonist); and (4) diazepam (2 and 5 mg/kg) and carbamazepine (5 and 20 mg/kg), two standard anticonvulsants, using the partially-kindled hippocampal model for epileptic seizures in freely moving rats. The anticonvulsant effect of these compounds were assessed by determining (1) the afterdischarge (AD), which is indicative of the severity of the seizure and related to seizure maintenance, and (2) the pulse number threshold (PNT), which is indicative of the seizure threshold or initiation. In addition, ataxia, a measure of CNS dysfunction, was assessed for each compound. Overall, our results indicated that the anticonvulsant compounds examined could be classified into three categories based on effects on the AD and PNT: (1) elevation of PNT (carbamazepine, dizocilpine, CGS 19755 and 7-chlorokynurenic acid); (2) reduction of AD (diazepam and muscimol); and (3) mixed action, i.e., increased PNT and decreased AD (YM90K). Behavioral data indicated that all compounds, except carbamazepine, produced a dose- or concentration-dependent ataxia. Overall, our results suggest that NMDA receptors play a role in seizure initiation, whereas the GABA(A) receptors appear to be involved in seizure maintenance and AMPA receptors may be involved in both phenomena.

Topics: Animals; Anticonvulsants; Ataxia; Carbamazepine; Diazepam; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; GABA Agonists; Hippocampus; Kynurenic Acid; Male; Muscimol; Pipecolic Acids; Quinoxalines; Rats; Rats, Wistar; Seizures

Among glutamate receptor subtypes, the N-methyl-D-aspartate (NMDA) receptor plays a key role in brain development and cognitive processes, and mediates excitotoxic injury. To test the hypothesis that prolonged seizures may affect NMDA receptor characteristics in the developing brain, a 30-min episode of generalized seizures was induced in rats at 5, 10, 15 and 25 d of age by i.p. administrations of bicuculline, NMDA receptors were analyzed using specific binding of [3H]-labeled (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene-5,10-imin e maleate (MK-801) in brain membrane preparations, and allosteric regulation was studied by addition of glutamate (10 microM) and glycine (10 microM). In control pups, total number of binding sites increased between 5 and 25 d, Bmax values varying from 1032 +/- 93 to 2311 +/- 449 fmol/mg protein, whereas receptor affinity decreased with age, the affinity constant (Kd) changing from 20.9 +/- 2.0 to 29.1 +/- 2.0 nM. Activation of NMDA receptors by glutamate and glycine led to age-dependent decreases in Kd values, from 30% at 5 d to 72% at 25 d. Seizures altered receptor density only at 5 d (by 40%). Receptor affinity was increased after seizures at 5, 15 and 25 d (from 12 to 60%). The capacity of receptor activation by glutamate and glycine was significantly reduced by seizures at 5 d. There was no change either in density nor affinity of receptors at 10 d. Therefore, as previously shown for central adenosine and benzodiazepine receptors, sustained seizures are able to alter the characteristics of NMDA receptors in a specific way depending on the maturational stage, suggesting developmental changes in the mechanisms of brain response to seizures.

Topics: Allosteric Regulation; Animals; Bicuculline; Binding Sites; Brain; Dizocilpine Maleate; Female; Glutamic Acid; Glycine; Kinetics; Ligands; Male; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

The present study investigated the role of NMDA (N-methyl-D-aspartate) receptors in the hypersusceptibility to seizures induced by the benzodiazepine inverse agonist DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) during diazepam withdrawal in mice, using behavioral and biochemical approaches. The seizure threshold of DMCM was markedly decreased during diazepam withdrawal, reflecting withdrawal hyperexcitability in response to physical dependence. The decrease in the seizure threshold of DMCM in diazepam-withdrawn mice was inhibited by the non-competitive NMDA receptor antagonists MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate; 50 microg/kg, s.c.) and ifenprodil (20 mg/kg, i.p.). The effective doses of these compounds were lower than those required to prevent DMCM-induced seizures in chronically vehicle-treated mice. Since MK-801 and ifenprodil do not only bind to NMDA receptors but also to sigma receptors, the present study also investigated the effects of sigma receptor ligands. The decrease in the seizure threshold of DMCM in diazepam-withdrawn mice was not modified by the sigma receptor agonist, (+)-pentazocine (5 mg/kg, s.c.), or the sigma receptor antagonist, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride; 5 mg/kg, i.p.). Furthermore, the latency to the expression of wild running induced by intracerebroventricular administration of NMDA (60 ng/mouse) was also significantly lower in diazepam-withdrawn mice than in vehicle-treated control mice. On the other hand, there was no difference in the spermidine concentration between vehicle-treated control and diazepam-withdrawn mice. In a receptor binding experiment, the Bmax value for [3H]-MK-801 binding was significantly increased in cerebrocortical tissues from diazepam-withdrawn mice, while the Kd value did not change in either group. However, the acute addition of a high concentration of diazepam (10 and 100 microM) in vitro did not alter [3H]-MK-801 binding in cerebrocortical membrane preparations. The behavioral experiments suggest that NMDA receptor antagonists may suppress benzodiazepine withdrawal responses, while the biochemical study reveals upregulation of the NMDA receptor, which may play an important role in the hypersusceptibility to DMCM-induced seizure in diazepam-withdrawn mice.

Topics: Animals; Anticonvulsants; Carbolines; Cerebral Cortex; Convulsants; Diazepam; Dizocilpine Maleate; Male; Membranes; Mice; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Seizures; Spermidine; Substance Withdrawal Syndrome; Up-Regulation

Pesticides acting at GABAA receptors may induce convulsions in man and animals, but the mechanisms responsible for their convulsant activity are not fully explained. The following excitatory amino acid antagonists were studied for their protective action in mice intoxicated with chlorinated hydrocarbon insecticide lindane (gamma-hexachlorocyclohexane): the competitive NMDA antagonist: 3-(2-carboxypiperazine-4-yl)propenyl-1- phosphonic acid (D-CPPene, 20 mg/kg), the non-competitive NMDA antagonist: dizocilpine (MK-801, 0.4 mg/kg), the glycine site antagonist of NMDA receptor: 2-phenyl-1,3-propane-diol dicarbamate (felbamate, 400 mg/kg) and the competitive AMPA antagonist: 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX, 100 mg/kg). Systemic administration of an antagonist prior to lindane resulted in a strong anticonvulsant effect. D-CPPene, MK-801 and NBQX produced a marked increase of CD50 values of lindane for clonic convulsions. All the antagonists protected animals against tonic convulsions. Toxicity of lindane was potently reduced, as assessed 2, 24 and 120 hr after administration of the pesticide. Our results demonstrate that excitatory amino acid antagonists reduce convulsant properties and toxicity of lindane, suggesting that excitatory amino acid neurotransmission may be involved in its central action.

Topics: Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Felbamate; Hexachlorocyclohexane; Insecticides; Lethal Dose 50; Male; Mice; Phenylcarbamates; Propylene Glycols; Quinoxalines; Seizures

Hyperbaric O2 exposure causes seizures by an unknown mechanism. Cerebral blood flow (CBF) may affect seizure latency, although no studies have demonstrated a direct relationship. Awake rats (male, Sprague-Dawley, 350-450 g), instrumented for measuring electroencephalographic activity (EEG) and CBF (laser-Doppler flowmetry), were exposed to 100% O2 at 4 or 5 atm (gauge pressure) until EEG seizures. Compression with O2 caused vasoconstriction to about 70% of control flow that was maintained for various times. CBF then suddenly, but transiently, increased at a time that was reliably related to seizure latency (r=0.8, p<0.01). Additional animals were treated with agents that have diverse pharmacology and their effects on CBF and latency were measured. Glutamate receptor antagonists MK-801 (1 or 4 mg/kg) and ketamine (20-100 mg/kg) significantly increased CBF by 60-80% and decreased seizure latency from about 17+/-8 min (+/-S.D.) in controls to 5+/-1 and 6+/-2 min, respectively. In opposite, a nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine (NNA)(25 mg/kg) decreased CBF by about 25% and increased time to seizure to 60+/-16 min. If these effects occur in humans, non-invasive measurement of CBF could potentially improve the safety and reliability of hyperbaric O2 usage in clinical and diving applications. It also appears that the effect of drugs on seizure latency can be explained, at least in part, by their effect on CBF.

Topics: Analysis of Variance; Animals; Cerebrovascular Circulation; Dizocilpine Maleate; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Hyperbaric Oxygenation; Ketamine; Male; Nitric Oxide Synthase; Nitroarginine; Quinoxalines; Rats; Rats, Sprague-Dawley; Reaction Time; Seizures

Epileptogenesis induced by electrical kindling of rats appears to be superior to the acute maximal electroshock seizure (MES) test in normal animals in predicting the efficacy and adverse effect potential of drugs in patients with partial epilepsy. Unfortunately, inclusion of such kindling models in primary screening is hampered by the laborious and expensive procedure of stimulation and recording with implanted brain electrodes. Furthermore the size of the rats excludes their use in initial testing where compound availability is often limited for the 'first batch synthesis'. The present study demonstrates that chronic electrical stimulation with corneal electrodes in mice can rapidly yield large numbers of kindled animals with a seizure phenomenology reflecting partial seizures in man. A pharmacological characterisation showed that corneally kindled mice can be used repeatedly for several drug experiments with reproducible results. The seizure protection and adverse effect potential obtained with proven antiepileptic drugs were similar to the effects observed in amygdala kindled rats and their corresponding clinical profile in partial epilepsy. Protection was obtained with vigabatrin and levetiracetam in this new model despite their lack of anticonvulsant activity in the acute MES test. Furthermore, in agreement with clinical findings with NMDA antagonists, MK-801 revealed more severe adverse effects in corneally kindled mice than in normal animals. These results suggest that corneal kindling of mice represents a sensitive and valid screening model for the identification of new therapies for partial epilepsy in man.

Topics: Amygdala; Animals; Anticonvulsants; Carbamazepine; Cornea; Disease Models, Animal; Dizocilpine Maleate; Drug Evaluation, Preclinical; Electric Stimulation; Electroshock; Epilepsies, Partial; gamma-Aminobutyric Acid; Kindling, Neurologic; Levetiracetam; Male; Mice; Piracetam; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Retina; Seizures; Sensitivity and Specificity; Time Factors; Valproic Acid; Vigabatrin

The effect of the noncompetitive N-methyl-d-aspartate (NMDA)-receptor antagonist MK-801 on seizures induced by hyperbaric oxygen in relation to changes in cerebral blood flow (CBF) was investigated. Rats were injected with MK-801 (0.005-8 mg/kg) 30 min before exposure to 100% O2 at 5 atm (gauge pressure). MK-801 administration resulted in a biphasic response in seizure latency. Doses of 0.1-4 mg/kg significantly decreased time to EEG and motor seizures, while 8 mg/kg had no effect on seizure latency. MK-801 had no effect on seizure duration. In a dose range 0.1-8 mg/kg MK-801 increased CBF in awake animals, which might be responsible for the decreased seizure latency. The gradual increase in seizure latency with increasing MK-801 doses suggests involvement of an additional factor probably related to the drug's anticonvulsive effect. Unlike MK-801, a competitive NMDA receptor antagonist, AP-7, at a dose 250 mg/kg had no effect on latency to seizures or CBF.

Topics: 2-Amino-5-phosphonovalerate; Analysis of Variance; Animals; Anticonvulsants; Cerebral Cortex; Cerebrovascular Circulation; Dizocilpine Maleate; Electroencephalography; Excitatory Amino Acid Antagonists; Hyperbaric Oxygenation; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Seizures

Sequential treatment of rats with low doses of lithium and pilocarpine, a high dose of pilocarpine, or continuous hippocampal stimulation [CHS] (9 epochs, 10 min each) is reported to result in status epilepticus (SE). We report a novel method to establish SE based on continuous ventral hippocampal stimulation (5 epochs) followed by low dose pilocarpine (40 mg/kg) challenge. Motor limbic seizures occured in all the control rats. The latency to spike activity was 15 +/- 1 min after pilocarpine administration. Ventral hippocampal [VHc] and cortical EEG recordings were used to monitor the protective effect of diazepam (5 mg/kg). Except phenobarbital, all the three drugs completely prevented all the phases of seizure activity. Initiation of spikes was significantly prolonged by phenobarbital pretreatment. Further study on the characteristics of these convulsions offers a unique possibility for the recognition of brain regions, pathways, and neurotransmitters engaged in the spread of seizures in this model.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dizocilpine Maleate; Electroencephalography; Hippocampus; Limbic System; Lithium; Male; Neuroprotective Agents; Phenobarbital; Pilocarpine; Rats; Rats, Wistar; Seizures; Status Epilepticus; Stereotyped Behavior

The effects of N-methyl-d-aspartate (NMDA) and non-NMDA receptor antagonists were compared on audiogenic seizures in the rats neonatally exposed to propylthiouracil (PTU). The rats treated with 0.02% PTU through mother's milk during days 0-19 after delivery showed a high incidence of audiogenic seizures consisting of running fit (RF) followed by generalized tonic-clonic seizure (GTCS) after matured. The systemic administration with MK-801, a NMDA receptor antagonist dose-dependently inhibited both RF and GTCS. NBQX (6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione), a non-NMDA receptor antagonist, when systemically administered, failed to block audiogenic seizures. Audiogenic seizures caused a marked induction of c-fos messenger RNA (mRNA) in septal nucleus, bed nucleus of stria terminalis, amygdaloid nuclei, peripeduncular nucleus, and inferior colliculus, which was almost completely blocked by the pretreatment with MK-801. Bilateral microinjection of MK-801 into the inferior colliculus showed a tendency for inhibiting GTCS, but not RF, whereas CPP (3-(R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid), a competitive NMDA receptor antagonist produced a significant inhibition against both RF and GTCS. These NMDA receptor antagonists administered into cisterna ambience, the floor of which is composed of inferior colliculus and neighboring structures, have shown potent blocking effects on both RF and GTCS. The present results suggest that NMDA receptors in the inferior colliculus, presumably in the subnucleus of external cortex may play the critical role in the initiation of audiogenic seizures in PTU-treated rats.

Topics: Acoustic Stimulation; Animals; Animals, Newborn; Cisterna Magna; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hypothyroidism; In Situ Hybridization; Inferior Colliculi; Microinjections; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

The effect of intrastriatal administration of glutaric acid (GTR), a metabolite that accumulates in glutaric acidemia type I (GA-I), on the behavior of adult male rats was investigated. After cannula placing, rats received unilateral intrastriatal injections of GTR buffered to pH 7.4 with NaOH or NaCl. GTR induced rotational behavior toward the contralateral side of injection and clonic convulsions in a dose-dependent manner. Rotational behavior was prevented by intrastriatal preadministration of DNQX and muscimol, but not by the preadministration of MK-801. Convulsions were prevented by intrastriatal preinjection of muscimol. This study provides evidence for a participation of glutamatergic non-NMDA and GABAergic mechanisms in the GTR-induced behavioral alterations. These findings may be of value in understanding the physiopathology of the neurological dysfunction in glutaric acidemia.

Topics: Animals; Behavior, Animal; Convulsants; Corpus Striatum; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; GABA Agonists; gamma-Aminobutyric Acid; Glutamates; Glutarates; Injections; Male; Muscimol; Quinoxalines; Rats; Rats, Wistar; Seizures; Stereotyped Behavior

Rats neonatally treated with 0.02% propylthiouracil (PTU) through mother's milk showed a high incidence of audiogenic seizures after maturation. These audiogenic seizures were differently modified by MK-801 and NBQX; while intraperitoneal MK-801 equally inhibited running fit (RF) and generalized tonic-clonic seizure (GTCS), NBQX administered into cisterna ambiens significantly inhibited RF but not GTCS. The possible involvement of glutamate receptors in the inferior colliculus was further investigated using naive Sprague-Dawley rats injected with NMDA, AMPA or cyclothiazide, known as an inhibitor of desensitization of AMPA action. All drugs tested successfully induced RF followed by GTCS, resembling audiogenic seizures in PTU-treated rats. However, sound stimulation could augment AMPA-induced, but not NMDA-induced GTCS. Systemic administration with MK-801 potently blocked GTCS induced by AMPA/cyclothiazide, but the same drug failed to block RF after intracisternal injection with AMPA/cyclothiazide. Furthermore, intracisternal administration with NBQX significantly inhibited only RF induced by AMPA/cyclothiazide. The present study suggests that: 1) glutamate receptors in the brainstem, possible in the inferior colliculus, play a crucial role in audiogenic seizures, namely the initiation of RF and propagation into GTCS; and 2) the initiation mechanism is regulated by both NMDA and AMPA receptors, whereas propagation is mainly controlled by NMDA receptors.

Topics: Acoustic Stimulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Benzothiadiazines; Brain Stem; Dizocilpine Maleate; Epilepsy, Tonic-Clonic; Excitatory Amino Acid Agonists; Inferior Colliculi; N-Methylaspartate; Neuroprotective Agents; Propylthiouracil; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Seizures

Seizures induced with Thiosemicarbaside, Pentylenetetrasole, N-methyl-D,L-aspartate were used as models. The NO content increased 4-5-fold in the brain cortex at the peak of seizures. The increase could be prevented by pre-treatment with N-nitro-L-arginine and the seizures were weakened. Anticonvulsant drugs reduced the seizure manifestations and partially prevented the NO generation enhancement. The latter seems to be involved in pathophysiological mechanisms underlying the seizures.

Topics: Animals; Anticonvulsants; Arginine; Convulsants; Dizocilpine Maleate; Electron Spin Resonance Spectroscopy; Electroshock; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Male; N-Methylaspartate; Nitric Oxide; Nitroarginine; Pentylenetetrazole; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Semicarbazides

Kainic acid-induced seizures, in adult rats produce neurodegeneration in the hippocampus followed by sprouting of the mossy fibres in the inner molecular layer of the dentate gyrus and changes in GAP-43 expression in the granule cells. In the present study we observed that 4 days after kainic acid injection a dense plexus of silver-impregnated degenerating terminals detected by Gallyas's method and a decrease of GAP-43 immunostaining was observed in the inner molecular layer of the dentate gyrus indicating deafferentiation of this region. This was associated with the formation of an intense GAP-43 immunostained band in the supragranular layer. MK-801, a non-competitive inhibitor of the NMDA receptor, which partially inhibited the behavioural seizures induced by KA, also protected from the inner molecular layer deafferentation and markedly reduced the expression of GAP-43 mRNA in the granule cells and the intense GAP-43 immunostained band in the supragranular layer, suggesting a relationship among these events. Two months after kainic acid injection the intense supragranular GAP-43 positive band was no longer evident but the whole inner molecular layer appeared more labelled in association with the formation of the collateral sprouting of the mossy fibres in the inner molecular layer as detected by Timm's staining. These effects were also markedly reduced by the pretreatment with MK-801. Taken together, these experiments indicate for the first time a direct relationship between the increase of GAP-43 immunostaining in the inner molecular layer of the dentate gyrus and the collateral sprouting of mossy fibres in this district in response to kainic acid induced seizures. This further supports the hypothesis that the early induction of GAP-43 in granule cells may be one of the molecular mechanisms required for the synaptic reorganization of the mossy fibres.

Topics: Animals; Dentate Gyrus; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; GAP-43 Protein; Hippocampus; Immunohistochemistry; In Situ Hybridization; Kainic Acid; Male; Membrane Glycoproteins; Nerve Fibers; Nerve Tissue Proteins; Neurofilament Proteins; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Seizures; Silver Staining; Synapses

1. The authors examined the anticonvulsant effects of MK-801 on the pilocarpine-induced seizure model. Intraperitoneal injection of pilocarpine (400 mg/kg) induced tonic and clonic seizure. Scopolamine (10 mg/kg) and pentobarbital (5 mg/kg) prevented development of pilocarpine-induced behavioral seizure but MK-801 (0.5 mg/kg) did not. 2. An electrical seizure measured with hippocampal EEG appeared in the pilocarpine-treated group. Scopolamine and pentobarbital blocked the pilocarpine-induced electrographic seizure, MK-801 treatment augmented the electrographic seizure induced by pilocarpine. 3. Brain damage was assessed by examining the hippocampus microscopically. Pilocarpine produced neuronal death in the hippocampus, which showed pyknotic changes. Pentobarbital, scopolamine and MK-801 protected the brain damage by pilocarpine, though in the MK-801-treated group, the pyramidal cells of hippocampus appeared darker than normal. In all treatments, granule cells of the dentate gyrus were not affected. 4. These results indicate that status epilepticus induced by pilocarpine is initiated by cholinergic overstimulation and propagated by glutamatergic transmission, the elevation of which may cause brain damage through an excitatory NMDA receptor-mediated mechanism.

Topics: Animals; Brain Damage, Chronic; Dizocilpine Maleate; Male; Pilocarpine; Rats; Rats, Sprague-Dawley; Seizures

Subtypes I, II and III of sodium channel alpha-subunit mRNAs were analyzed in adult rat brain areas after kainate-induced seizures. Tissue samples were microdissected from occipital neocortex, CA1 and CA3 hippocampus areas and dentate gyrus. Three reverse transcriptase-polymerase chain reaction (RT-PCR) protocols were undertaken to amplify these mRNAs. Amplification products were then distinguished after digestion by restriction enzymes, electrophoresis separation and densitometric analysis of gel profiles. PCR 1 evidenced the relative percentage of mRNAs I, II and III as well as neonatal II and III subtype isoforms, which resulted from an alternative splicing. PCR 2 and 3 were performed to focus on the neonatal vs. adult ratio in II and III subtypes, respectively. Seizures were shown to induce an increase in both neonatal subtypes, which suggested an alteration at the splicing level. These changes exhibited a peculiar brain regional distribution, the maximal effect being observed in dentate gyrus and hippocampus CA1 area. In situ hybridization experiments, using a digoxigenin-labeled oligonucleotide probe-specific for neonatal II and III mRNAs, confirmed this increase in neonatal mRNA subtypes. These changes were transient, reaching a maximum 6 h after drug injection, then disappearing between 12 and 48 h. They were prevented by a pre-treatment of animals by MK-801, a non-competitive antagonist of NMDA receptors. This work, thus, suggested that KA-induced seizures can be accompanied by transient alteration in the splicing pattern of sodium channel alpha-subunit mRNAs which resulted in an increase in expression of their neonatal isoforms within localized areas of adult rat brain.

Topics: Animals; Animals, Newborn; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Genetic Code; Hippocampus; In Situ Hybridization; Kainic Acid; Male; Neuroprotective Agents; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA, Messenger; Seizures; Sodium Channels; Transcription, Genetic

To investigate the effects of a new non-NMDA antagonist on the trisynaptic pathways in the hippocampus, the author examined the kainate(KA)-induced generalized seizures in rats. A novel non-NMDA antagonist, YM90K, showed the blockade of the Schaffer collaterals in a 2-deoxyglucose study (2-DG) and that the CA1-2 pyramidal cells of the hippocampus were preserved seven days after the KA injections. On the other hand, the control and MK-801 (NMDA-antagonist) treated rats did not depress the Schaffer collaterals and showed persistent hypermetabolism of glucose in the CA1 pyramidal cell layer, where neurons were not preserved seven days later. 2-DG was useful to reveal the effects of a non-NMDA antagonist on the KA-induced generalized seizures. This suggests that YM90K is a potent non-NMDA antagonist and that it has a neuroprotective effect in rats.

Topics: Animals; Anticonvulsants; Brain; Dizocilpine Maleate; Glucose; Hippocampus; Kainic Acid; Male; N-Methylaspartate; Quinoxalines; Rats; Rats, Sprague-Dawley; Seizures

Kainic acid (KA) causes behavioral and electrographic status epilepticus (SE) in rats of all ages. In adult rats, the noncompetitive N-methyl-D-aspartate (NMDA) channel blocker MK801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine ) is anticonvulsant against KA-induced seizures: it reduces their severity and protects against neuronal damage, although it may worsen electrographic seizures. Here we examined the effects of MK801 on KA seizures in the immature brain. Neonatal rats (P11-P12) were pretreated with MK801 (0.01, 0.1, 0.5 or 1.0 mg/kg, i.p.) or saline twenty minutes prior to KA (2 mg/kg, i.p.). Clinical seizure behavior was monitored for > 6 hrs, and in some rats the EEG was monitored with an intrahippocampal or intracortical electrode. MK801 caused immobility alternating with hyperactivity, ataxia, scratching and sometimes alternate limb cycling, which correlated with the appearance of spikes on the EEG. Compared to KA alone or KA preceded by 0.01 mg/kg MK801, the higher doses of MK801 (0.1, 0.5 and 1.0 mg/kg) significantly lowered the latency to electrographic seizures (P < 0.001), ictal scratching (P < 0.0001), and status epilepticus (P < 0.0001). MK801 pretreatment did not lower significantly the death rate due to KA seizures. No histologic damage was seen after MK801, KA or both agents together. These results suggest that MK801 exacerbates KA-induced seizures in the neonatal brain, and may even cause ictal behavioral and electrographic manifestations by itself. The findings point to an age-dependency of NMDA antagonist action, and suggest caution in considering the use of NMDA antagonists in neonates.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroencephalography; Kainic Acid; Male; Rats; Rats, Sprague-Dawley; Reaction Time; Seizures; Time Factors

We investigated the role of the NMDA receptor complex in DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate)-induced seizures in mice. The seizure threshold of DMCM was evaluated using an i.v. infusion technique. Pretreatment with the non-competitive NMDA receptor antagonist MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d) cycloheptan-5,10-imine maleate) or phencyclidine (PCP) significantly increased the seizure threshold for DMCM. Furthermore, the seizure threshold of DMCM was increased by intracerebroventricular (i.c.v.), but not intrathecal (i.t.), pretreatment with MK-801. Moreover, 7-chlorokynurenic acid, a glycine site antagonist, also increased the seizure threshold of DMCM, whereas ifenprodil, a non-competitive polyamine site antagonist, did not. These findings indicate that the ion-channel binding site and the glycine binding site on the NMDA receptor complex in the brain may be involved in the expression of seizures induced by DMCM.

Topics: Animals; Carbolines; Cerebral Ventricles; Convulsants; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Infusions, Intravenous; Injections, Intraventricular; Injections, Spinal; Kynurenic Acid; Male; Mice; Mice, Inbred Strains; Phencyclidine; Piperidines; Receptors, N-Methyl-D-Aspartate; Seizures; Spinal Cord

Effects of both acute and long-term treatments with a non-competitive NMDA-antagonist, MK-801, were studied in rats in order to investigate whether NMDA receptors would be involved in the maintenance of kindling. Intraperitoneally administered MK-801 at doses of 0.5, 1.0 and 2.0 mg/kg inhibited fully amygdaloid kindled seizures (stage 5) behaviorally and significantly reduced the duration of after discharge and postictal spikes in a dose-dependent manner. Long-term (28 days) administration of MK-801 at three dosages neither abolished behavioral kindled seizures nor significantly altered generalized seizure thresholds. However the after discharge duration and postictal spikes were significantly reduced in rats treated with MK-801 at doses of 0.5 and 1.0 mg/kg, while no significant alterations were observed in rats treated with saline or MK-801 at a dose of 2.0 mg/kg. Acute effects of MK-801 suggested that NMDA receptors were involved in the maintenance of kindling. On the other hand, long-term treatments with MK-801 remained to show such an unequivocal effect.

Topics: Amygdala; Animals; Behavior, Animal; Brain; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroencephalography; Excitatory Amino Acid Antagonists; Kindling, Neurologic; Male; Rats; Rats, Wistar; Seizures; Time Factors

This study was designed to investigate the influence of the calcium (Ca2+) channel inhibitors nicardipine, nifedipine, and flunarizine on the protective action of MK-801, LY 235959 [N-methyl-D-aspartate (NMDA) receptor antagonists], and GYKI 52466 (a non-NMDA receptor antagonist) against electroconvulsions in mice. Unlike nicardipine (15 mg/kg) or flunarizine (10 mg/kg) nifedipine (7.5 and 15 mg/kg) potentiated the protective potency of MK-801 (0.05 mg/kg), as reflected by significant elevation of the convulsive threshold (a CS50 value of the current strength in mA producing tonic hind limb extension in 50% of the animals). The protective activity of LY 235959 and GYKI 52466 was reflected by their ED50 values in mg/kg, at which the drugs were expected to protect 50% of mice against maximal electroshock-induced tonic extension of the hind limbs. Nicardipine (3.75 15 mg/kg), nifedipine (0.94-15 mg/kg), and flunarizine (2.5-10 mg/kg) in a dose-dependent manner markedly potentiated the antiseizure efficacy of LY 235959. Flunarizine (5 and 10 mg/kg) was the only Ca2+ channel inhibitor to enhance the protective action of GYKI 52466 against electroconvulsions. Except with MK-801 + flunarizine (motor performance) or GYKI 52466 + flunarizine (long-term memory), combination of NMDA or non-NMDA receptor antagonists with Ca2+ channel inhibitors produced an impairment of motor performance (evaluated in the chimney test) and long-term memory acquisition (measured in the passive avoidance task) as compared with vehicle treatment.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Avoidance Learning; Benzodiazepines; Calcium Channel Blockers; Dizocilpine Maleate; Drug Interactions; Electroshock; Excitatory Amino Acid Antagonists; Flunarizine; Isoquinolines; Male; Mice; Motor Activity; Nicardipine; Nifedipine; Seizures

The effects of several NMDA receptor antagonists on pentylenetetrazole-induced diazepam-withdrawal seizure were examined in mice. The decrease in the seizure threshold for pentylenetetrazole during diazepam withdrawal was inhibited by pretreatment with MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate), 7-chlorokynurenic acid and ifenprodil. Furthermore, MK-801 and ifenprodil, at doses which did not affect the threshold of pentylenetetrazole-induced seizure in control mice, also significantly suppressed the decrease in the seizure threshold during diazepam withdrawal, whereas 7-chlorokynurenic acid did not. These findings suggest that overactivity of an ion channel site and an ifenprodil binding site on the NMDA receptor may play an important role in the hypersensitivity of pentylenetetrazole-induced seizure in diazepam-withdrawn mice.

Topics: Animals; Anticonvulsants; Convulsants; Diazepam; Disease Models, Animal; Dizocilpine Maleate; Drug Interactions; Excitatory Amino Acid Antagonists; Infusions, Intravenous; Injections, Intraperitoneal; Injections, Subcutaneous; Kynurenic Acid; Male; Mice; Neuroprotective Agents; Pentylenetetrazole; Piperidines; Receptors, N-Methyl-D-Aspartate; Seizures; Substance Withdrawal Syndrome

The effects of pilocarpine- and kainate-induced seizures on N-methyl-D-aspartate receptor subunit-1 messenger RNA and [3H]dizocilpine maleate binding were studied in the rat hippocampal formation. Pilocarpine- but not kainate-induced seizures decreased N-methyl-D-aspartate receptor subunit-1 messenger RNA level in dentate gyrus at 24 and 72 h after drug injection. Both convulsants decreased the messenger RNA level in CA1 pyramidal cells at 24 and 72 h, the effects of kainate being more profound. Kainate also decreased the N-methyl-D-aspartate receptor subunit-1 messenger RNA level in CA3 region after 24 and 72 h, whereas pilocarpine decreased the messenger RNA level at 72 h only. At 3 h after kainate, but not pilocarpine, an increased binding of [3H]dizocilpine maleate in several apical dendritic fields of pyramidal cells was found. Pilocarpine reduced the [3H]dizocilpine maleate binding in stratum lucidum only at 3 and 24 h after the drug injection. Pilocarpine but not kainate induced prolonged decrease in N-methyl-D-aspartate receptor subunit-1 gene expression in dentate gyrus. However, at the latest time measured, kainate had the stronger effect in decreasing both messenger RNA N-methyl-D-aspartate receptor subunit-1 and [3H]dizocilpine maleate binding in CA1 and CA3 hippocampal pyramidal cells. The latter changes corresponded, however, to neuronal loss and may reflect higher neurotoxic potency of kainate. These data point to some differences in hippocampal N-methyl-D-aspartate receptor regulation in pilocarpine and kainate models of limbic seizures. Moreover, our results suggest that the N-methyl-D-aspartate receptor subunit-1 messenger RNA level is more susceptible to limbic seizures than is [3H]dizocilpine maleate binding in the rat hippocampal formation.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Gene Expression; Hippocampus; Kainic Acid; Male; Pilocarpine; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Seizures

Alpha-dendrotoxin (alpha-DTx), a snake venom toxin which blocks several types of fast-activating voltage-dependent potassium channels, induces limbic seizures and neuronal damage when injected into the brain. The mechanisms underlying these convulsant and neuropathological actions are not fully understood. We have studied the effects of alpha-DTx on neurotransmitter release and electrical activity in rat hippocampal brain slices and the role of excitatory amino acid receptors in mediating these actions of the toxin. alpha-DTx increased the basal release of acetylcholine, glutamate, aspartate, and GABA in a concentration-dependent manner and induced epileptiform bursting in the CA1 and CA3 regions of the slice. The increase in neurotransmitter release was evident during the first 4 min after toxin addition, whereas the bursting appeared after a concentration-dependent delay (20-40 min with 250 nM toxin). The N-methyl-D-aspartate (NMDA) receptor antagonists AP5 and MK-801 had no effect on the frequency or amplitude of dendrotoxin-induced epileptiform bursts, but the non-NMDA antagonists CNQX and DNQX abolished bursting in both CA1 and CA3 within 4-6 min. In contrast, the toxin-induced increases in neurotransmitter release were not blocked by DNQX. This study has demonstrated that, following exposure to alpha-DTx, there is a rapid increase in the release of neurotransmitters which precedes the onset of epileptiform bursting in the hippocampus. Since DNQX abolished the bursting but had no effect on the increase in neurotransmitter release, these results suggest that DNQX blocks alpha-DTx-induced epileptiform activity by antagonism of postsynaptic non-NMDA receptors.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Acetylcholine; Action Potentials; Animals; Aspartic Acid; Dizocilpine Maleate; Elapid Venoms; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Hippocampus; Male; Neurotoxins; Neurotransmitter Agents; Potassium Channels; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

We previously demonstrated that 2-iminothiazolidine-4-carboxylic acid (2-ICA), formed by cyanide reacting with cysteine, caused glutamate antagonist-sensitive seizures when injected i.c.v. (intracerebroventricular) in mice and produced hippocampal CA1 damage following i.c.v. infusion in rats. In this study, the ability of either 2-ICA, glutamate, proline or NMDA (N-methyl-D-aspartate) injected i.c.v. to produce hippocampal lesions sensitive to glutamate antagonists was compared in mice. Hippocampal CA1 damage was observed 5-days following either a seizure (3.2 mumol) or subseizure (1.0 mumol) dose of 2-ICA. Glutamate (3.2 mumol) or proline (10 mumol) also produced hippocampal damage; glutamate damage was primarily to the CA1 subfield, whereas proline damaged neurons throughout the entire hippocampal formation. NMDA (3.2 nmol) caused seizure activity in all animals with a 50% lethality. No hippocampal damage was observed in surviving mice. Neither MK-801 (dizocilpine maleate) nor CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) pretreatment prevented hippocampal lesions produced by 2-ICA. In contrast, MK-801 significantly reduced the frequency of mice displaying glutamate hippocampal lesions, but failed to block seizures produced by glutamate. MK-801 also protected neurons in the CA2-3 zone and the dentate gyrus, but not in the CA1 region of proline-injected mice. Finally, pretreatment with the mixed metabotropic glutamate receptor (mGluR)1/mGluR2 antagonist-agonist (S)-4-carboxy-3-hydroxyphenylglycine (CHPG) prevented hippocampal damage produced by the mGluR1 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG), but did not protect against 2-ICA hippocampal lesions. These results show that 2-ICA hippocampal CA1 damage is not mediated through ionotropic or metabotropic glutamate receptors. 2-ICA hippocampal damage may represent a neurotoxicity that is distinct from excitotoxic-mediated cell death.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Brain Ischemia; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Glutamic Acid; Hippocampus; Injections, Intraventricular; Male; Neuroprotective Agents; Neurotoxins; Proline; Rats; Rats, Sprague-Dawley; Seizures

Seizures were induced in immature 18-day-old rats by i.p. administration of homocysteine (11 mmol/kg) and the effects of selected antagonists of NMDA receptors [MK-801 (0.5 mg/kg), AP7 (0.33 mmol/kg), CGP 40116 (10 mg/kg)] and non-NMDA receptors [GDEE (4 mmol/kg), NBQX (two doses, 30 mg/kg each)] were studied. The effect of MgSO4 (two doses, 2 mmol/kg each) was also tested. The anticonvulsant effect was evaluated not only from the behavioral manifestations of seizures, but also in terms of some indicators of brain energy metabolism. Rat pups were sacrificed during generalized clonic-tonic seizures, corresponding to 16-45 min after homocysteine administration. Comparable time intervals were used for sacrificing the pups which had received the protective drugs. In contrast to neonatal rats, in which only NMDA antagonists could prevent homocysteine-induced seizures, both NMDA and non-NMDA receptor antagonists exerted an anticonvulsant effect in 18-day-old rats. In addition, the pronounced anticonvulsant effect could be achieved by the combined treatment with low subthreshold doses of NMDA (MK-801) and non-NMDA (NBQX) receptor antagonists. The protection was evident not only in suppressing behavioral symptoms of seizures, but also in preventing most of the metabolic changes accompanying seizures, mainly glycogen degradation. More than a sevenfold accumulation of lactate occurring during seizures was markedly reduced by all the tested drugs, but was not completely eliminated. All antagonists, when given alone in the same doses as those used for seizure protection, remained without any effect on lactate levels. Comparison of the present data with previous findings concerning neonatal rats suggests that there may be a developmental change in anticonvulsant efficacy of non-NMDA receptor antagonists against homocysteine-induced seizures in rats.

Topics: 2-Amino-5-phosphonovalerate; Age Factors; Animals; Anticonvulsants; Behavior, Animal; Brain Chemistry; Dizocilpine Maleate; Dose-Response Relationship, Drug; Energy Metabolism; Excitatory Amino Acid Antagonists; Glutamates; Homocysteine; Male; Neuroprotective Agents; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

The ion channel of the N-methyl-D-aspartate (NMDA) receptor complex is subject to a voltage-dependent regulation by Mg2+ cations. Under physiological conditions, this channel is supposed to be blocked by a high concentration of magnesium in extracellular fluids. A single dose of magnesium organic salts (i.e., aspartate, pyroglutamate, and lactate) given orally to normal mice rapidly increases the plasma Mg2+ level and reveals a significant dose-dependent antagonist effect of magnesium on the latency of NMDA-induced convulsions; this effect is similar to that seen after administration of the dizocilpine (MK-801) channel blocker. An anticonvulsant effect of Mg2+ treatment is also observed with strychnine-induced convulsions but not with bicuculline-, picrotoxin-, or pentylenetetrazol-induced convulsions. In the forced swimming test, Mg2+ salts reduce the immobility time in a way similar to imipramine and thus resemble the antidepressant-like activity of MK-801. This activity is masked at high doses of magnesium by a myorelaxant effect that is comparable to MK-801-induced ataxia. Potentiation of yohimbine fatal toxicity is another test commonly used to evaluate putative antidepressant drugs. Administration of Mg2+ salts, like administration of imipramine strongly potentiates yohimbine lethality in contrast to MK-801, which is only poorly active in this test. Neither Mg2+ nor MK-801 treatment can prevent reserpine-induced hypothermia. These data demonstrate that oral administration of magnesium to normal animals can antagonize NMDA-mediated responses and lead to antidepressant-like effects that are comparable to those of MK-801. This important regulatory role of Mg2+ in the central nervous system needs further investigation to evaluate the potential therapeutic advantages of magnesium supplementation in psychiatric disorders.

Topics: Adrenergic alpha-Agonists; Animals; Body Temperature; Depression; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Female; Magnesium; Male; Mice; Mice, Inbred Strains; Motor Activity; Psychomotor Performance; Receptors, N-Methyl-D-Aspartate; Reserpine; Seizures; Sympatholytics; Yohimbine

We recently reported that scopolamine pretreated mice fasted for 48 h developed clonic convulsions soon after they were allowed to eat a small amount of food for 30 s. The present experiments were performed to determine whether animals also develop convulsions when they were allowed to eat ad libitum and to find some evidence for the contribution of the cholinergic and/or glutamatergic systems in the underlying mechanism(s) of convulsions. Animals fasted for 48 h were treated with 3 mg/kg scopolamine or saline. Twenty minutes later, they were allowed to eat either ad libitum or a small portion of food for 30 s. Scopolamine pretreated animals after starting to eat ad libitum or a small amount in a restricted time developed convulsions in a few minutes, the incidence being 76 and 54%, respectively. Pretreatment of 0.17 mg/kg MK-801, the noncompetitive NMDA antagonist, decreased the incidence of scopolamine-induced convulsions (22%) without affecting latency to the onset of seizures. Pretreatment of 0.1 mg/kg physostigmine, the cholinesterase inhibitor, changed neither the incidence (90%) nor latency to the onset of scopolamine-induced convulsions.

Topics: Animals; Cholinesterase Inhibitors; Dizocilpine Maleate; Eating; Male; Mice; Physostigmine; Scopolamine; Seizures

1. Contribution of nitric oxide to the convulsive seizures induced by fluoroquinolones (FQs) coadministered with 4-biphenyl acetic acid (BPAA), the active metabolite of fenbufen, was assessed in mice. 2. Enoxacin + 4-biphenyl acetic acid caused clonic seizures in all treated mice, followed by tonic seizures and death. These events were associated with a significant increase in intracerebellar cyclic GMP. 3. Pretreatment with the nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methylester (L-NAME), but not with D-NAME, significantly reduced the incidence of convulsions and lethality, as well as the increase in cyclic GMP. 4. Pretreatment with N-methyl-D-aspartic acid (NMDA)-receptor antagonist, MK-801, inhibited only the transition of clonic seizure to tonic seizure without affecting the incidence of clonic seizure and lethality. 5. These findings suggest that FQs + BPAA exert convulsions by activating NOS partly through the mediation of the NMDA receptor in the brain cells.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Ciprofloxacin; Convulsants; Cyclic AMP; Dizocilpine Maleate; Enoxacin; Enzyme Inhibitors; Male; Mice; Mice, Inbred Strains; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Ofloxacin; Phenylacetates; Seizures

2,3-Dihydro-6,7-dichloro-pyrido[2,3-b]pyrazine-8-oxide was synthesized and evaluated for in vitro/in vivo antagonistic activity at the strychnine insensitive glycine binding site on the NMDA receptor revealing it to be a useful tool to evaluate the effectiveness of glycine antagonists in vivo.

Topics: Animals; Avoidance Learning; Binding Sites; Cyclic N-Oxides; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glycine; Kynurenic Acid; Mice; Motor Activity; N-Methylaspartate; Neuroprotective Agents; Pyrazines; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Stereotyped Behavior; Strychnine

A series of 1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and evaluated for anticonvulsant activity against intracerebro-ventriculas (i.c.v.) N-methyl-D-aspartate (NMDA)-induced seizures in mice. Among these compounds, (+)-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride ((+)-1a, FR115427) was the most effective anticonvulsant, and also protected CA1 hippocampal neurons from ischemia-induced neuronal degeneration in rats at 32 mg/kg i.p. In addition, (+)-1a showed anti-hypoxic activity in mice at 3.2-32 mg/kg i.p. The absolute configuration at the C-1 position of the isoquinoline ring was determined to be S by a single-crystal X-ray analysis of (+)-1a (+)-di-p-toluoyl-D-tartrate. Structure-activity relationships with regard to the anticonvulsant activity of this series of compounds are discussed, and the three-dimensional structures of (S)-(+)-1a and MK801 are compared.

Topics: Animals; Anticonvulsants; Brain Ischemia; Crystallography, X-Ray; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Hypoxia; Isoquinolines; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred ICR; Molecular Structure; Neuroprotective Agents; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Stereoisomerism; Structure-Activity Relationship; Tetrahydroisoquinolines

Subcutaneous injection of potassium cyanide (6, 8, and 9 mg/kg) caused a severe tonic seizure in a dose-dependent manner. However, the incidence of seizures induced by potassium cyanide was significantly inhibited by preadministration of melatonin (20 mg/kg, s.c.) Lipid peroxidation in homogenates from whole brain of mice was significantly increased (39%, 106% and 132%, respectively) by the exposure to potassium cyanide (0.01, 0.05, and 0.1 mM). The potassium cyanide (0.1 mM)-induced lipid peroxidation was prevented by melatonin (0.1, 0.5, 1.0, or 2 mM) in a concentration-dependent manner. These results suggest that free radicals formation and subsequent lipid peroxidation may contribute in part to the development of seizures induced by cyanide in mice.

Topics: Animals; Cyanides; Dizocilpine Maleate; Dose-Response Relationship, Drug; Lipid Peroxidation; Male; Melatonin; Mice; Mice, Inbred Strains; Seizures

1. The involvement of the N-methyl-D-aspartate (NMDA) receptor macrocomplex in the development of spermine-induced CNS excitation in vivo was investigated. 2. Injection of 100 micrograms of spermine into the left lateral cerebral ventricle of female Laca mice (20-25 g) resulted in the development of two distinct phases of CNS excitatory effects which were quantified by a scoring system. 3. The first phase effects occurred within minutes of injection and generally lasted for about 1 h. Most mice showed scratching of the upper body, frequent face washing and some mice developed clonic convulsions. By about 2 h after injection, the second phase of effects began to develop in the form of body tremor which worsened with time and culminated in fatal tonic convulsions, generally within 8 h of injection. 4. Pretreatment of the mice with dizocilpine (0.3 mg kg-1, i.p.) resulted in antagonism of the first phase of spermine-induced effects, but a higher dose (0.3 mg kg-1, (x2), i.p.) was necessary to inhibit the second phase effects. 5. Whereas the glutamate antagonist, 3-((R)-2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (D-CPP) (10, 20 mg kg-1, i.p.), the glycine antagonist 7-chlorokynurenate (10, 30, 50 nmol, i.c.v.), or the polyamine antagonist ifenprodil (30, 60 mg kg-1, i.p.) antagonized the first phase of effects produced by spermine, these agents given as monotherapy, were ineffective against the development of the second phase of effects. 6. Co-administration of ifenprodil with either D-CPP or 7-chlorokynurenate resulted in a dose-dependent antagonism of the development of the second phase of spermine-induced effects. 7. It is concluded that the development of the two temporally distinct phases of spermine-induced effects may be mediated by pharmacologically distinct mechanisms, although the results suggest that the NMDA receptor macrocomplex may be involved in both phases of effects. Furthermore, a moderate dose of D-CPP or 7-chlorokynurenate appears to enhance the inhibitory potential of ifenprodil in vivo.

Topics: Animals; Brain; Cerebral Ventricles; Dizocilpine Maleate; Female; Kynurenic Acid; Mice; Neuroprotective Agents; Piperazines; Piperidines; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Seizures; Spermine; Tremor

The effect of MK-801, a non-competitive N-methyl-D-aspartate (NMDA) antagonist, on the kainic acid-induced expression of the inducible heat shock protein 70 kDa (HSP70) and on neuronal death in the rat hippocampus was investigated. HSP70 is expressed in approximately 80% of the pyramidal neurons in the CA1 field 1 day after kainic acid injection. The majority of these HSP70-immunopositive neurons exhibited swelling and a hollow appearance in the perikaryon, indicating that they had been injured following kainic acid-elicited limbic seizures. Four days after administration of kainic acid, 87% of the pyramidal neurons in the CA1 field were dead. When a single dose of MK-801 was administered 1 h before kainic acid injection, the number of rats suffering with seizures was reduced, the severity of limbic seizures was attenuated and seizure onset was delayed. Neither HSP70 expression on day 1 nor neuronal loss on day 4 in the CA1 pyramidal cell layer was observed in these animals. A considerable number of HSP70-immunopositive neurons was detected in the dentate hilus, however, and somewhat fewer in the CA3a and CA3c subfields on day 1. Severe neuronal damage in these regions followed on day 4. Interestingly, little HSP70 expression or neuronal loss was observed in the CA3b subfield in these same animals. When a single dose of MK-801 was given 4 h after kainic acid treatment, HSP70 expression was partially blocked; 18% of neurons expressed HSP70 on day 1 and 37% on day 4 in CA1 pyramidal neurons in comparison to the kainic acid controls. About 50% neuronal death was detected in the CA1 pyramidal cell layer 4 days after kainic acid treatment followed by MK-801. When the animals were treated with MK-801 4 h after kainic acid treatment followed by additional daily administration for 3 days, a negligible number of pyramidal neurons expressed HSP70, and the survival of pyramidal cells was significantly increased in the CA1 field. Limbic seizure-induced HSP70 expression not only indicates neuronal injury in the pyramidal cell layer of the hippocampus but also predicts delayed neuronal death, at least in the case of the CA1 field of animals that suffered stage IV-V seizures.

Topics: Animals; Cell Death; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Heat-Shock Proteins; Hippocampus; Immunohistochemistry; Kainic Acid; Male; Neuroprotective Agents; Rats; Rats, Wistar; Seizures

The effect of intrastriatal administration of methylmalonic acid (MMA), a metabolite that accumulates in methylmalonic aciduria, on behavior of adult male Wistar rats was investigated. After cannula placing, rats received unilateral intrastriatal injections of MMA (buffered to pH 7.4 with NaOH) or NaCl. MMA induced rotational behavior toward the contralateral side of injection and clonic convulsions in a dose-dependent manner. Rotational behavior and convulsions were prevented by intrastriatal preadministration of MK-801 and attenuated by preadministration of succinate. This study provides evidence for a participation of NMDA receptors in the MMA-induced behavioral alterations, where succinate dehydrogenase inhibition seems to have a pivotal role.

Topics: Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Indicators and Reagents; Male; Methylmalonic Acid; Microinjections; Neostriatum; Rats; Rats, Wistar; Rotation; Seizures; Stereotyped Behavior; Succinate Dehydrogenase

A failure of early paired pulse depression often precedes the onset of intermittent spontaneous seizures in animal models of status epilepticus. In the present study, changes in the strength of early and late paired pulse depression of dentate granule cell field potentials were compared in the unanesthetized rat during the initiation of a single afterdischarge (AD) evoked by perforant path stimulation (0.1 ms pulse duration, 5 Hz, 12-18 s duration, 50-1000 microA). Late paired pulse depression was measured by sequential changes in the population spike (PS) amplitude during 5 Hz stimulation (200 ms interpulse interpulse interval, IPI). When 5 Hz stimulation triggered an AD, the population spike (PS) was initially depressed and then increased to above pre-train values, indicating a loss of late paired pulse depression by the middle of the train. Early paired pulse depression was measured by inserting paired pulses (20 ms IPI) at spaced intervals throughout the 5 Hz train. In contrast to late paired pulse depression, early paired pulse depression remained at maximum strength until an abrupt failure was detected coincident with AD initiation. Two experimental treatments shown to increase the strength of late paired pulse depression, administration of the N-methyl-D-aspartate antagonist, MK-801 (0.25 mg/kg, i.p.), and the development of kindled seizures, produced an increase in AD thresholds and in the initial depression in the PS amplitude during 5 Hz stimulation. Together, these results suggest that a failure of late paired pulse depression may be a precipitating event in AD initiation triggered by 5 Hz stimulation in the unanesthetized rat.

Topics: Action Potentials; Animals; Anticonvulsants; Dentate Gyrus; Differential Threshold; Dizocilpine Maleate; Electric Stimulation; Hippocampus; Kindling, Neurologic; Male; Neurons; Rats; Rats, Inbred Strains; Seizures; Time Factors

The effects of NMDA receptor antagonists on the convulsant action of the administration of 4-aminopyridine in the rat lateral cerebral ventricle (i.c.v. injection) and motor cerebral cortex (i.cx. injection) were studied. 4-Aminopyridine administration in both regions induced various preconvulsive symptoms, such as salivation, tremors, chewing and rearing, followed by continuous clonic convulsions and, only after i.c.v. injection, running fits and generalized tonic convulsions. This behavioral pattern appeared 5-9 min after administration of 4-aminopyridine and persisted for 100-150 min. 4-Aminopyridine also generated epileptiform electroencephalographic (EEG) discharges characterized by isolated spikes, poly-spikes and spike-wave complexes, which began some seconds after administration of the drug and were present for more than 2 h. The NMDA receptor antagonists (+/-)-3-(2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP), (+/-)-2-amino-7-phosphono-heptanoic acid (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) clearly protected against some of the behavioral alterations induced by i.c.v. 4-aminopyridine, particularly the tonic convulsions, but were less effective against those produced by i.cx. 4-aminopyridine. These antagonists also delayed the appearance of EEG epileptiform discharges, reduced its amplitude, frequency and duration, and blocked their propagation to other cortical regions after i.cx. 4-aminopyridine. These results, together with previous data showing that 4-aminopyridine stimulates the release of glutamate in vivo, suggest that an excessive glutamatergic neurotransmission involving NMDA receptors is implicated in 4-amino-pyridine-induced seizures.

Topics: 2-Amino-5-phosphonovalerate; 4-Aminopyridine; Animals; Anticonvulsants; Convulsants; Dizocilpine Maleate; Electroencephalography; Injections, Intraventricular; Male; Motor Cortex; Neuroprotective Agents; Piperazines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Stereotaxic Techniques

During repeated alcohol withdrawal, convulsive withdrawal behavior has been shown to be increased in a kindling-like manner in both clinical and experimental studies. In the present experiment, quantitative autoradiography was used to investigate binding of tritiated ligands to glutamate receptor subtypes and the benzodiazepine/GABA (BZ/GABA) receptor complex in rats exposed to 14 episodes of alcohol withdrawal. Seizures were detected in 25% of the animals during withdrawal episode 10-13. Repeated alcohol withdrawal resulted in a decrease in the number of [3H]-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]-AMPA) binding sites in striatum and sub-regions of the entorhinal cortex, the cerebellum and the hippocampus, while the [3H]-flunitrazepam binding was down-regulated in the frontal cortex. There was no differences between the controls and the multiple withdrawal animals regarding the [3H]-dizocilpine ([3H]-MK801) binding and the [3H]-kainic acid binding. However, within the latter group, those animals in which withdrawal seizures were observed had increased [3H]-MK801 binding sites in focal regions of entorhinal cortex and hippocampus, compared to those in which seizures were not observed. The decreased AMPA binding suggested impaired glutamate neurotransmission. As such, this receptor probably did not contribute to alcohol withdrawal kindling, but rather was involved in seizure protective mechanisms during this process.

Topics: Alcoholism; Animals; Autoradiography; Brain; Dizocilpine Maleate; Down-Regulation; Ethanol; Excitatory Amino Acid Antagonists; Flunitrazepam; GABA Modulators; Kindling, Neurologic; Male; Rats; Rats, Wistar; Receptors, GABA-A; Receptors, Glutamate; Receptors, Kainic Acid; Seizures; Substance Withdrawal Syndrome

Because of the critical role of excitatory amino acids (EAAs) in epileptogenesis and seizure-induced brain damage, EAA antagonists are now being considered as a possible therapy for seizures. However, during development EAAs play a pivotal role in learning, memory, and brain plasticity. To evaluate the long-term effects of a short course of EAA antagonists on the developing brain, a non-NMDA antagonist, NBQX, or a NMDA antagonist, MK-801, were administered over 7 days by osmotic pumps stereotaxically implanted into the lateral ventricles of normal 10 day old rats. Alternatively, 10 and 20 day old rats received a 7 day course of intraperitoneal (i.p.) NBQX. One month later, the NBQX-, MK-801-treated rats, and controls underwent a series of behavioral studies: handling test, open field, and Morris water maze. Flurothyl inhalation was used to test seizure susceptibility in all groups. Although all of the rats treated with NBQX via osmotic pumps has spontaneous seizure, rats surviving infusion of EAAs had no deficits in learning, memory, or behavior and did not differ from controls in seizure susceptibility with flurothyl. In the developing animal, a short-term course of EAA antagonists leads to no long-term adverse effects on behavior or seizure susceptibility.

Topics: Animals; Animals, Newborn; Brain; Dizocilpine Maleate; Evaluation Studies as Topic; Excitatory Amino Acid Antagonists; Exploratory Behavior; Infusion Pumps, Implantable; Injections, Intraperitoneal; Male; Maze Learning; Neuroprotective Agents; Pilot Projects; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

Cessation of chronic administration of orally administered large amounts of ethanol for 7 days resulted in a markedly increased frequency of audiogenic seizures in Sprague-Dawley rats. Oral administration of the novel glycine receptor antagonist, L-701,324, produced a dose-dependent (2.5 and 5.0 mg/kg; -30 min) inhibition of ethanol withdrawal signs when measured about 12 h after withdrawal of the ethanol treatment. Similarly, using the same experimental paradigm, oral administration of the specific polyamine receptor antagonist, eliprodil, caused a dose-related (2.0 and 5.0 mg/kg; -30 min) inhibition of ethanol withdrawal-induced audiogenic seizure activity. The inhibition of ethanol withdrawal seizures produced by L-701,324 and eliprodil, respectively, was obtained at doses which by themselves did not change the locomotor activity in naive Sprague-Dawley rats. The findings that L-701,324 and eliprodil are potent inhibitors of seizure activity induced by cessation of chronic ethanol administration and the fact that they, in contrast to currently available NMDA receptor antagonists, do not produce psychotomimetic and/or sedative effects, suggest that these drugs may represent a new class of therapeutically useful pharmacological agents for the treatment of ethanol withdrawal seizures. Furthermore, since there is evidence that eliprodil produces its pharmacological actions through a specific inhibition of NMDAR1 and/or NMDAR2B subunits, these data may indicate that certain NMDA receptor subunits may be of particular importance for the mediation of seizure activity following the discontinuation of chronic ethanol exposure.

Topics: Acoustic Stimulation; Administration, Oral; Animals; Anticonvulsants; Central Nervous System Depressants; Dizocilpine Maleate; Ethanol; Excitatory Amino Acid Antagonists; Male; Motor Activity; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Seizures; Substance Withdrawal Syndrome

The NMDA receptor plays an important role in patterning neural connectivity in the developing brain. In the adult brain, repeated kindling stimulation of limbic pathways increases the NMDA-dependent component of synaptic transmission in granule cells of the dentate gyrus (DG) and also induces sprouting of the mossy fiber axons of granule cells that reorganizes synaptic connections in the DG. Because the NMDA antagonist MK801 impedes the progression of kindling, it was of interest to determine whether MK801 also modified mossy fiber sprouting. Low doses of MK801, which had no antiseizure effect, impaired the progression of kindling and development of mossy fiber sprouting during the initial and also more advanced stages of kindling. These observations demonstrate that the NMDA receptor is a component of a molecular pathway that influences the progression of kindling and mossy fiber sprouting and suggest that NMDA-dependent gene expression may play a role in the development of long-term structural and functional alterations induced by seizures in hippocampal circuitry. The NMDA receptor appears to play a continuing role in modifying the organization and patterns of connectivity in hippocampal circuits of the adult brain.

Topics: Age Factors; Animals; Cell Division; Dentate Gyrus; Dizocilpine Maleate; Electric Stimulation; Excitatory Amino Acid Antagonists; Kindling, Neurologic; Male; Nerve Fibers; Neurons; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Time Factors

The involvement of kainate (KA)-sensitive regions in ethanol withdrawal behaviors was investigated in male Wistar rats given three intraperitoneal (IP) injections of KA (12 mg/kg) or saline each followed by recovery at 4 degrees C for 5 h and room temperature for 3 days and a final KA or saline injection at room temperature. Some animals received MK-801 (1 mg/kg, IP) 30 min after each injection and one group received saline only. The saline/saline, saline/MK-801, and KA/MK-801 groups displayed typical ethanol withdrawal behaviors 8-12 h after ethanol withdrawal. These behaviors were attenuated in the KA/saline group. Audiogenic seizures could be induced in all treatment groups 12 h after withdrawal. There was severe neuronal degeneration in the hippocampal CA region and the piriform cortex of the KA/saline-treated animals that was reduced by MK-801 treatment. The inferior colliculus remained intact. These results suggest that the N-methyl-D-aspartate receptor mediates KA-induced damage in limbic structures and that these regions may play an important role in typical, but not audiogenically induced ethanol-withdrawal behaviors.

Topics: Animals; Behavior, Animal; Cerebral Cortex; Cold Temperature; Dizocilpine Maleate; Ethanol; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Hippocampus; Kainic Acid; Male; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Substance Withdrawal Syndrome

Pretreatment of DBA/2 mice (n = 14-15 per group) with an 18-mer antisense probe to the NMDA-receptor submit NR1 (2 x 1 micrograms, or 2 x 83 pmol, NR1 antisense probe intracerebroventricularly, -29 and -7 h before testing for seizure response) resulted in almost complete suppression of sound-induced clonic seizures. A saline-treated group gave a 100% seizures response, while the group treated with NR1 antisense probe gave a 7% seizure response to the sound stimulus. The group treated with NR1 nonsense-probe showed no anticonvulsant protection (93% seizure response). The anticonvulsant protection observed following NR1 antisense administration was of relatively short duration, with seizure response gradually returning to control levels 12 to 24 h following the termination of antisense administration. When NR1 receptor levels were assessed by receptor autoradiography ([3H]-MK 801 and -CGP 39653 binding) in the same groups of mice, significant (20%) reductions in NR1 levels were observed in the retrosplenial cortex and the overall cortex. The seizure-induced expression of c-fos and NGFI-A in thalamus, hypothalamus, inferior colliculus and medical geniculate seen in vehicle- and NR1 nonsense-treated mice was completely blocked by NR1 antisense pretreatment.

Topics: Acoustic Stimulation; Animals; Antisense Elements (Genetics); Autoradiography; Cerebral Cortex; Codon, Nonsense; Dizocilpine Maleate; Female; Genes, Immediate-Early; Inferior Colliculi; Male; Mice; Mice, Inbred DBA; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Seizures

Endothelin (ET) is a potent vasoconstrictor which has also been proposed to act as a neuromodulator. We have investigated the action of ET-1 on neurones in vivo, using c-fos as a marker of neuronal activation. Intrastriatal injection of ET-1 caused seizures and barrel rolling which were prevented by pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and attenuated by the nitric-oxide synthase inhibitor N omega-nitro-L-arginine (L-NNA). In association with these behaviours, a dramatic increase in c-fos mRNA expression was seen in the cerebral cortex. This increase was blocked by both MK-801 and L-NNA. We suggest that ET-1 modulates the activity of cortical afferents to the striatum, and causes seizures via an NMDA receptor-dependent mechanism.

Topics: Animals; Cerebral Cortex; Dizocilpine Maleate; Endothelin-1; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Hippocampus; In Situ Hybridization; Injections; Male; Neostriatum; Nitric Oxide Synthase; Nitroarginine; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

Dizocilpine has been shown to be anticonvulsant in several experimental models of epilepsy. Nevertheless, 0.3 or 0.5 mg/kg intraperitoneal (i.p.) dizocilpine produced cortical spike-wave discharges (SWDs) in four of seven rats. The SWDs were accompanied by behavioral arrest, and also showed: a narrow range of induction times (around 25 min post-injection); hippocampal spikes closely correlated with the cortical spikes of the SWDs; a precipitous drop out of fast (45-100 Hz) cortical EEG; myoclonic bursts in nuchal EMG that began during the cortical slow waves. These findings suggest that patients being treated experimentally for stroke with non-competitive N-methyl-D-aspartate (NMDA) cation channel blockers should be monitored for seizures.

Topics: Animals; Dizocilpine Maleate; Electroencephalography; Electromyography; Evoked Potentials; Injections, Intraperitoneal; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Seizures

The effects of ethanol, glycine, and spermidine on the specific binding of [3H]MK-801 were characterized in Triton-treated membranes prepared from the hippocampus and cortex of ethanol-withdrawal seizure-prone (WSP) and -resistant (WSR) mice. Glycine, an allosteric agonist at the NMDA receptor-linked ion channel complex, caused an increase in specific [3H]MK-801 binding to hippocampal membrane preparations. There were no significant differences in EC50 values between the selected lines for the effect of glycine (WSP, 391.7 +/- 48.4 nM; WSR, 313.4 +/- 77 nM) in the presence of 10 microM NMDA or in the maximal response to the agonist (WSP, 1.75 +/- 0.26 pmol/mg of protein; WSR, 1.67 +/- 0.22 pmol/mg of protein). The EC50 values for the spermidine-induced increase in [3H]MK-801 binding in membranes from hippocampus in the absence (WSP, 11.7 +/- 0.83 microM; WSR, 9.98 +/- 1.29 microM) or in the presence of 10 microM glycine and 10 microM NMDA (WSP, 2.1 +/- 0.35 microM; WSR, 2.37 +/- 0.42 microM) also did not differ. Similar results were obtained in cortical membranes. Saturation isotherms indicated that there was no difference in the density of [3H]MK-801 binding sites, or in their affinity for the radioligand, between the mouse lines. In addition, administration of ethanol by inhalation (24 h) to WSP and WSR mice did not cause an increase in the density of [3H]MK-801 binding sites, and there was no difference in the density or affinity of binding sites between the mouse lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Allosteric Regulation; Animals; Cerebral Cortex; Dizocilpine Maleate; Ethanol; Genetic Predisposition to Disease; Glycine; Hippocampus; Ion Channels; Male; Mice; Mice, Mutant Strains; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Seizures; Spermidine; Substance Withdrawal Syndrome

ADCI (5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine), a low-affinity uncompetitive N-methyl-D-aspartate (NMDA) antagonist, is a broad-spectrum anticonvulsant with a favorable side-effect profile. In the present study, we sought to determine if tolerance develops to the anticonvulsant activity of ADCI, using the maximal electroshock (MES) test to assess seizure protection. Mice were treated with three daily injections of a 2 x ED50 dose for MES protection (18 mg/kg, intraperitoneally, i.p.) or vehicle for 7 or 14 days. On the day after the chronic treatment protocol, all animals received a challenge dose of ADCI (18 mg/kg) and 15 min later were evaluated in the MES test. In control animals, 83-94% of animals were protected and the ADCI plasma levels immediately after the MES test were 5.5-9.7 micrograms/ml. In treated animals, 29 and 0% of animals were protected at 7 and 14 days, respectively, and the ADCI plasma levels were 77 and 52% of the control values. [3H]Dizocilpine binding to brain NMDA receptors was unaltered by the chronic drug treatment. In subsequent experiments, we determined that 14-day chronically treated animals could be completely protected by increased doses of ADCI (ED50 28.9 mg/kg). In both naive and chronically treated animals receiving a challenge dose of ADCI, plasma drug levels decreased in two phases, the first with a time constant of approximately 55 min and the second with a much slower rate. The estimated plasma concentrations of ADCI reflecting threshold (3-5 micrograms/ml) and 50% protection (5-7.5 micrograms/mg) were similar in naive and chronic animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anticonvulsants; Brain; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Tolerance; Electroshock; Male; Mice; Receptors, N-Methyl-D-Aspartate; Seizures

Excitatory amino acid (EAA)-like and excitotoxic properties of the secondary metabolite of cyanide, 2-iminothiazolidine-4-carboxylic acid, (2-ICA) were evaluated because of its possible role in cyanide-induced neurotoxicity. Intracerebroventricular (i.c.v.) injections of 2-ICA in mice produced wild-running seizures that were qualitatively and quantitatively similar to seizures observed with glutamate. 2-ICA, kainate and proline seizures were prevented by both the NMDA and non-NMDA antagonists, MK-801 and CNQX, respectively. In contrast, NMDA-induced seizures were prevented by MK-801, but not CNQX. When infused i.c.v. in rats over a seven day period, 2-ICA produced extensive and selective loss of CA-1 pyramidal neurons of the hippocampus. In hippocampal slices preloaded with D-[3H]aspartate, 2-ICA superfusion did not evoke release nor significantly augment potassium stimulated release of the radiolabeled transmitter. These findings indicate 2-ICA has excitotoxic properties and its role in cyanide neurotoxicity deserves further study.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Carboxylic Acids; Cyanides; Dizocilpine Maleate; Dose-Response Relationship, Drug; Glutamic Acid; Hippocampus; Proline; Rats; Rats, Sprague-Dawley; Seizures

Mice were exposed to an atmosphere consisting of 7% O2 and 93% N2 or 5.5% O2 and 94.5% N2 for 60 min. The susceptibility of the mice to the convulsive effect of pentylenetetrazol (PTZ) was decreased, in comparison to that of naive or sham-exposed controls, 1 and 7 days after exposure to 7% O2. A significant protective effect against PTZ-induced seizures was not observed in mice exposed to 5.5% O2. N-methyl-D-aspartate (NMDA) administrated immediately after exposure to the hypoxic atmosphere, had no significant influence on the protective effect of hypoxia. Treatment of naive or sham-exposed mice with NMDA resulted in protection against PTZ-induced seizures when they were tested 7 days later. Dizolcipine (MK 801), at a dose of 0.01 mg/kg injected i.p. 10 min before hypoxia, abolished the protective effect of hypoxia; higher doses (0.1 or 0.3 mg/kg) of MK 801 were not effective. The adenosine A1 receptor antagonist 1,3-diethyl-8-phenylxanthine (DPX), administered at a dose of 0.1 mg/kg s.c. before hypoxia, blocked the decrease in the susceptibility to the convulsive effect of PTZ. DPX also blocked the protective effect, seen after 7 days, of NMDA given to control mice. These results suggest that both NMDA and adenosine A1 receptor-mediated processes were involved in the protective effect of moderate hypoxia against PTZ-evoked seizure.

Topics: Animals; Dizocilpine Maleate; Excitatory Amino Acid Agents; Hypoxia; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Pentylenetetrazole; Receptors, Purinergic; Seizures; Time Factors; Xanthines

Some non-DBA2 Albino Swiss mice exhibit noise induced epileptic seizures during a short period of postnatal development. Because N-methyl-D-aspartate (NMDA) glutamate ionotropic receptors are involved in the occurrence of audiogenic seizures, we investigated by in situ hybridization methods, the expression of the different subunits (NR1, NR2A, NR2B, NR2C) of this receptor in the central nucleus of the inferior colliculus (IC), a main relay of the auditory pathways. At postnatal day 20, the NR2C subunit is highly expressed in the IC of convulsive mice, while in non-convulsive mice a slight signal is only found for NR1, NR2A, and NR2B. In adult mice, the NR1 and NR2A signals are observed while the NR2B signal is almost undetectable. The audiogenic susceptibility may be related to the transient expression of the NR2C subunit during a brief neonatal period during which synaptic reorganization happens.

Topics: Acoustic Stimulation; Animals; Autoradiography; Base Sequence; Brain Stem; Dizocilpine Maleate; In Situ Hybridization; In Vitro Techniques; Inferior Colliculi; Mice; Mice, Inbred DBA; Molecular Sequence Data; Neuronal Plasticity; Oligonucleotide Probes; Receptors, N-Methyl-D-Aspartate; Seizures; Species Specificity

Cocaine produces not only euphoric effects but also a wide range of detrimental effects, including seizures and lethality. The present study examined the involvement of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptors and the dopamine D1 and D2 receptors in seizure activity and lethality observed following single and repeated injections of cocaine in ddY mice. Repeated injections of 60 mg/kg cocaine resulted in the development of sensitization to the convulsant effects of cocaine during an initial 3 or 4 days, followed by the development of tolerance at day 5 and day 6. Repeated injections of 90 mg/kg cocaine augmented the lethal effect of cocaine progressively over the course of treatment. Treatment with 0.1-0.4 mg/kg of the noncompetitive NMDA receptor antagonist, MK-801, prevented the development of sensitization to cocaine-induced seizures in a dose-dependent manner, and attenuated partially the cocaine-induced lethality. In contrast, treatment with 10-50 mg/kg of the dopmaine D2 receptor antagonist, sulpiride, had no effects on the development of sensitization and tolerance to cocaine-induced seizures. On the other hand, treatment with 0.1-0.5 mg/kg of the dopamine D1 receptor antagonist, SCH 23390, not only prolonged the latency to 90 mg/kg cocaine-induced seizures but also delayed the development of sensitization to the convulsant effects of cocaine. The increased lethality observed following repeated injection of cocaine was unaffected by treatment with SCH 23390, but was severely aggravated by treatment with sulpiride.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzazepines; Cocaine; Dizocilpine Maleate; Dopamine Antagonists; Dose-Response Relationship, Drug; Kindling, Neurologic; Male; Mice; Mice, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Seizures; Sulpiride; Time Factors

Tolerance occurred to the sedative actions of the competitive NMDA antagonists, CGP39551 and CGP37849, as measured by a decrease in spontaneous locomotor activity after 1 week or 2 weeks of administration, respectively, in studies using the TO strain of mice. Crosstolerance was seen between these compounds. When CGP37849 was given after 2 weeks treatment with CGP39551, an increase in locomotor activity was seen. Chronic barbiturate treatment, producing tolerance to the actions of pentobarbitone, did not affect the sedative properties of CGP39551 or CGP37849. Chronic treatment with CGP39551 did not alter the ataxic actions of pentobarbitone. Seven days of treatment with HA966 caused complete tolerance to its sedative actions, but no crosstolerance was seen to pentobarbitone, CGP39551, or CGP37849. A small but significant decrease was seen in the convulsion thresholds to NMDA after 15 days of treatment with CGP39551, and a small significant increase in ratings of convulsive behavior after 16 days injections of CGP37849. No significant changes were found in either Bmax or Kd for [3H]-MK-801 binding in cerebrocortical tissue 24 h after the last chronic treatment with either of the NMDA antagonists.

Topics: 2-Amino-5-phosphonovalerate; Animals; Ataxia; Behavior, Animal; Dizocilpine Maleate; Drug Tolerance; Hypnotics and Sedatives; Male; Mice; Motor Activity; N-Methylaspartate; Pyrrolidinones; Receptors, N-Methyl-D-Aspartate; Seizures; Substance Withdrawal Syndrome

The behavioural and convulsant effects of imipenem (Imi), a carbapenem derivative, were studied after intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. The anticonvulsant effects of some excitatory amino acid antagonists and muscimol (Msc), a GABAA agonist, against seizures induced by i.p. or i.c.v. administration of Imi were also evaluated. The present study demonstrated that the order of anticonvulsant activity in our epileptic model, after i.p. administration, was (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine maleate (MK-801) > (+/-)(E)-2-amino-4-methyl-5-phosphono-3-pentenoate ethyl ester (CGP 39551) > 3-((+/-)-2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid (CPPene) > 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CCP) > 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline (NBQX). Ifenprodil, a compound acting on the polyamine site of NMDA receptor complex was unable to protect against seizures induced by Imi, suggesting that the poliamine site did not exert a principal role in the genesis of seizures induced by Imi. In addition, the order of anticonvulsant potency in our epileptic model, after i.c.v. administration, was CPPene > MK-801 > Msc > (-)-2-amino-7-phosphonic acid (AP7) > gamma-D-glutamylaminomethylsulphonate (gamma-D-GAMS) > NBQX > kynurenic acid (KYNA) > 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX). The relationship between the different site of action and the anticonvulsant activity of these derivatives was discussed. Although the main mechanism of Imi induced seizures cannot be easily determined, potential interactions with the receptors of the excitatory amino acid neurotransmitters exists. In fact, antagonists of excitatory amino acids are able to increase the threshold for the seizures or to prevent the seizures induced by Imi. In addition, Imi acts on the central nervous system by inhibition of GABA neurotransmission and Msc, a selective GABAA agonist, was able to protect against seizures induced by Imi.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Amino Acids; Animals; Anticonvulsants; Dizocilpine Maleate; Excitatory Amino Acids; Glutamine; Imipenem; Kynurenic Acid; Mice; Mice, Inbred DBA; Muscimol; Piperazines; Piperidines; Quinoxalines; Seizures

Hyperthermia-induced seizures (HS) in rats have been used as a model of febrile seizures. Activation of the N-methyl-D-aspartate (NMDA) receptor by increased extracellular glutamate (Glu) in the cortex during hyperthermia may be involved in the induction of HS and HS kindling. To confirm this hypothesis, the effects of a potent blocker of the NMDA receptor, MK-801, on the threshold and pattern of HS were evaluated. The threshold temperatures for rats given 0.1 (low dose) and 0.5 (high dose) mg/kg MK-801 (i.p.) for the first time were 41.6 degrees C (39.7-42) (median, range) and 42.0 (41.2-42.0), respectively, which were significantly higher than the 40.5 (39.4-41.2) for rats without MK-801 administration (P < 0.01). The recurrent occurrence of HS suppressed the increase in the threshold temperature with age, and changed the seizure from partial to generalized seizures (HS kindling), whereas these effects of recurrent HS on the threshold and pattern of HS were inhibited by the high dose (0.5 mg/kg) of MK-801. MK-801 blocks HS and HS kindling. The activation of the NMDA receptor during hyperthermia plays an important role in the induction of HS and HS kindling.

Topics: Age Factors; Animals; Dizocilpine Maleate; Fever; Glutamic Acid; Kindling, Neurologic; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

The regional expression of inducible 72 kDa heat shock protein (HSP-70), HSP-70 mRNA and the neuropathological outcome of their expression were examined in the rat brain following systemic administration of kainic acid (9 mg/kg), and also after pretreatment with the non-competitive N-methyl-D-aspartate antagonist MK-801 (1 mg/kg). Five hours after administration of kainic acid alone, dense expression of HSP-70 mRNA was found within the limbic system, mainly in the hippocampus, piriform and entorhinal cortices, amygdaloid complex, thalamic nuclei, subiculum and in other cortical areas in rats that had shown convulsive behaviour. At 24 h, HSP-70 immunoreactivity was seen in most areas previously expressing HSP-70 mRNA, except the piriform and entorhinal cortices and several ventral nuclei of the amygdaloid complex. Histopathological examination at 24 h revealed marked cell loss in these latter regions and less severe histopathological changes in other areas of the limbic system in brains of convulsive rats. No alterations were apparent in non-convulsive rats. The percentage of rats showing convulsive behaviour with kainic acid was reduced from 74 to 4% following pretreatment with MK-801. In addition, MK-801 inhibited the kainic acid-induced expression of HSP-70 mRNA and protein in certain brain regions, notably the cortex, the pyramidal cell layer of CA1, and discrete thalamic nuclei. However, HSP-70 mRNA induction was sustained in the pyramidal cell layer of CA3, the amygdaloid complex and the subiculum, despite the fact that none of these rats convulsed. MK-801 prevented necrosis in all rats examined except the single rat that had shown convulsive behaviour. These results show that early regional expression of inducible HSP-70 mRNA allows the visualization of regions affected by kainic acid and maps regions inhibited by MK-801. In addition, the results identify brain regions putatively involved in the manifestation of limbic convulsions. Furthermore, these data illustrate that the induction of HSP-70 mRNA is not predictive of cell death or survival.

Topics: Animals; Behavior, Animal; Body Temperature; Brain; Brain Mapping; Dizocilpine Maleate; HSP70 Heat-Shock Proteins; Immunohistochemistry; In Situ Hybridization; Kainic Acid; Male; Nerve Tissue Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures

The release of cholecystokinin (CCK) in vitro has been shown to be influenced by NMDA receptors. In this study we have investigated whether excitotoxin-induced seizure activity affects the release and tissue content of CCK. Excitotoxin injection caused a significant decrease in CCK in ipsilateral frontal, parietal and temporal cortex by (30-54%) at 8 h compared to contralateral cortex and sham-operated controls and the effect was reversed by 24 h. No change was detected in occipital cortex, hippocampus and nucleus accumbens. The effect in frontal and temporal cortex was maximal at 8 h and could be completely prevented by treatment with MK-801(3 mg/kg i.p.). Anaesthesia (pentobarbital) alone or in combination with MK-801 did not affect peptide levels at 8 h. CCK mRNA levels were also studied quantitatively by slot-blot analysis but were unaffected at 6, 8 and 24 h after excitotoxin injection. The decrease in CCK tissue levels indicated that seizure activity stimulated CCK release which was confirmed in ex vivo experiments where K(+)-evoked (34 mM) CCK release was significantly enhanced in ipsilateral cerebral cortex at 6 h compared to contralateral cortex.

Topics: Animals; Cerebral Cortex; Cholecystokinin; Dizocilpine Maleate; Frontal Lobe; Hippocampus; Immunoblotting; Kainic Acid; Male; Nucleus Accumbens; Potassium; Radioimmunoassay; Rats; RNA, Messenger; Seizures; Temporal Bone

We determined the effects of the N-methyl-D-aspartate (NMDA) receptor blocker MK-801 (0.05, 0.1, and 0.5 mg/kg intraperitoneally, i.p.) and phenytoin (PHT, 5, 10, and 20 mg/kg i.p.) on flurothyl-induced clonic and tonic-clonic seizures in 9-, 15-, 30-, and 60-day-old male rats. Both agents had seizure-, age-, and dose-specific effects. The highest dose of MK-801 was anticonvulsant against clonic flurothyl-induced seizures only in 9- and 60-day-old rats, but suppressed tonic-clonic seizures in all ages. The lowest dose of MK-801 (0.05 mg/kg) produced significant anticonvulsant effects only in 15 day old rats. PHT did not have any effect on clonic seizures throughout development. Both doses of PHT (10 and 20 mg/kg) were anticonvulsant against tonic-clonic seizures in adult rats but not in any other age group. The results indicate that NMDA receptors play an important role in tonic-clonic flurothyl-induced seizures throughout development (especially in 15-day-old rats) and that the anticonvulsant effects of PHT may vary at different stages of brain development.

Topics: Age Factors; Animals; Brain; Dizocilpine Maleate; Dose-Response Relationship, Drug; Epilepsy, Tonic-Clonic; Flurothyl; Male; Phenytoin; Rats; Receptors, N-Methyl-D-Aspartate; Seizures

The nucleus reticularis pontis oralis (RPO) is necessary for the expression of tonic hindlimb extension (THE) in maximal electroshock (MES) seizures of rats. Previous work in this laboratory has demonstrated that both systemic administration and focal RPO microinfusion of D-cycloserine inhibits THE. The purpose of the present study was to characterize specific components of the NMDA receptor/ionophore complex that regulate the anticonvulsant activity mediated by the RPO. Bilateral RPO microinfusion of the competitive NMDA antagonists (-)AP7 and D-CPP as well as the uncompetitive antagonist dizocilpine ((+)MK-801) inhibited THE in a dose-related fashion. Bilateral RPO microinfusion of NMDA did not affect the THE response to MES but did induce convulsions resembling audiogenic seizures in genetically epilepsy prone rats. Bilateral RPO microinfusion of the strychnine-insensitive glycine site partial agonist D-cycloserine and the antagonist 5,7-dichlorokynurenic acid inhibited THE. The strychnine-insensitive glycine partial agonists (+)HA-966 and ACPC, as well as the agonists glycine and D-serine, did not significantly affect the THE response. Strychnine microinfusions in the RPO had no effect on THE. The results support a hypothesis that the RPO is a site of anticonvulsant drug action in MES and indicate that either competitive or uncompetitive NMDA antagonist action regulates the anticonvulsant activity mediated by the RPO. The role of the strychnine-insensitive glycine site in the regulation of the anticonvulsant activity medicated by the RPO is uncertain.

Topics: Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroshock; Male; N-Methylaspartate; Pons; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Strychnine

Intracerebroventricular administration to mice of 5,7-dihydroxytryptamine at a dose of 300 micrograms resulted in convulsive behaviour and death (latency 7.6 +/- 1.7 min.). Pretreatment with dizocilpine or chlormethiazole resulted in a dose dependent inhibition of the convulsive behaviour. A dose of dizocilpine of 0.12 mumol/kg or chlormethiazole at a dose of 150 mumol/kg prevented seizures for 30 min. Injection of 5,7-dihydroxytryptamine (75 micrograms, intracerebroventricularly) produced an approximate 50% neurotoxic loss of cerebral 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA) 8 days later. This loss was not prevented by administration of either dizocilpine (4.5 mumol/kg intraperitoneally) or chlormethiazole (300 mumol/kg intraperitoneally) given 5 min. before and 55 min. after the 5,7-dihydroxytryptamine injection. It is proposed that chlormethiazole and dizocilpine may protect against 5,7-dihydroxytryptamine-induced seizures because of their anticonvulsant activity, but that they do not prevent the neurotoxic effects of the compound. The data also suggest that the neurotoxic effects of substituted amphetamines such as 3,4-methylene dioxymethamphetamine (MDMA or Ecstasy) do not result from the formation of a 5,7-dihydroxytryptamine like compound.

Topics: 5,7-Dihydroxytryptamine; Animals; Behavior, Animal; Brain; Chlormethiazole; Dizocilpine Maleate; Hydroxyindoleacetic Acid; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Seizures; Serotonin

Physical dependence on ethanol can result in seizure susceptibility during ethanol withdrawal. In rats, generalized tonic-clonic seizures are precipitated by auditory stimulation during the ethanol withdrawal syndrome. Excitant amino acids (EAAs) are implicated as neurotransmitters in the inferior colliculus and the brain stem reticular formation, which play important roles in the neuronal network for genetic models of audiogenic seizures (AGSs). Ethanol blocks the actions of EAAs in various brain regions, including the inferior colliculus. In this study, dependence was produced by intragastric administration of ethanol for 4 days. During ethanol withdrawal, AGSs were blocked by systemic administration of competitive or noncompetitive NMDA antagonists 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) or dizocilpine (MK-801). Focal microinjections of NMDA or non-NMDA antagonists into the inferior colliculus or the pontine reticular formation also inhibited AGSs. MK-801 was the most potent anticonvulsant systemically. When injected into the inferior colliculus, CPP had a more potent anticonvulsant effect than either MK-801 or the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. The inferior colliculus was more sensitive than the pontine reticular formation to the anticonvulsant effects of both competitive NMDA and non-NMDA antagonists. The results of the present support the idea that continued ethanol administration may lead to development of supersensitivity to the action of EAAs in inferior colliculus and pontine reticular formation neurons. This may be a critical mechanism subserving AGS susceptibility during ethanol withdrawal.

Topics: Acoustic Stimulation; Alcohol Withdrawal Delirium; Animals; Anticonvulsants; Brain Mapping; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy, Tonic-Clonic; Ethanol; Evoked Potentials; Excitatory Amino Acids; Injections; Male; Piperazines; Pons; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reticular Formation; Seizures

The effects of two non-competitive NMDA antagonists--MK-801 and ketamine--were studied in a model of generalized seizures elicited by s.c. injection of strychnine (2 or 3 mg/kg) in adult rats. The animals were observed in isolation for 30 min after strychnine administration. Pretreatment with MK-801 (0.5 or 2 mg/kg i.p.) suppressed the tonic, but not the clonic phase of generalized seizures following both doses of strychnine. A similar action of ketamine (20 or 40 mg/kg i.p.) was indicated but it did not attain statistical significance. Strychnine-induced lethality was not changed significantly. A comparison with antiepileptic drugs demonstrated that only phenobarbital (10-80 mg/kg i.p.) was clearly effective against strychnine-induced seizures; carbamazepine (25 or 50 mg/kg i.p.) and partly phenytoin (30 or 60 mg/kg i.p.) were able to suppress the incidence of the tonic phase. Primidone (40 or 80 mg/kg i.p.) as well as the benzodiazpines bretazenil (0.1 or 1 mg/kg i.p.) and midazolam (two lower doses of 0.5 and 1 mg/kg i.p.) were without significant effect. The 2 mg/kg dose of midazolam was partly effective. Only phenobarbital, carbamazepine and the highest dose of midazolam prevented strychnine-induced lethality.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dizocilpine Maleate; Ketamine; Male; Rats; Rats, Wistar; Seizures; Strychnine

Homocysteine induces seizures in adult, as well as in immature, experimental animals, but the mechanism of its action is still unknown. The aim of the present study was to examine whether homocysteine in immature animals may act via excitatory amino acids receptors. Seizures were induced in 7-day-old rats by ip administration of homocysteine (16.5 mmol/kg) and the effects of selected antagonists at NMDA and non-NMDA receptor sites were investigated. The anticonvulsant effect was evaluated not only in terms of behavioral changes, but also in terms of some indicators of brain energy metabolism. Rat pups were sacrificed during generalized clonic-tonic seizures, corresponding approximately to 15-30 min after homocysteine administration. Comparable time intervals were used for sacrificing pups in the groups with protective drugs. Non-NMDA antagonists, L-glutamic acid diethylester (GDEE) (4 mmol/kg, ip) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline (NBQX) (two doses, 30 mg/kg each, ip), failed to protect neonatal rats against homocysteine-induced seizures. Although NBQX prevented the tonic phase, the severity of clonic movements was even more pronounced. Metabolic changes accompanying the seizures (decreases of glucose and glycogen and a rise of lactate) were also not influenced by GDEE or NBQX pretreatment. On the contrary, NMDA antagonists, both competitive (AP7, 0.33 mmol/kg, ip) and noncompetitive (MK-801, 0.5 mg/kg, ip), had a clear-cut anticonvulsant effect. They not only suppressed the behavioral signs of seizures, but also prevented most of the metabolic changes accompanying seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Animals, Newborn; Anticonvulsants; Dizocilpine Maleate; Glutamates; Homocysteine; Male; Neuroprotective Agents; Quinoxalines; Rats; Rats, Wistar; Receptors, Amino Acid; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Seizures

The biologically active enantiomer (CGP 40116) of the new competitive N-methyl-D-aspartate (NMDA) receptor antagonist CGP 37849 was investigated for its effects on pilocarpine-induced limbic motor seizures and unconditioned motor behaviour in the mouse. CGP 40116 (1-8 mg/kg IP) reduced the incidence and severity of pilocarpine-induced motor seizures, although the overall effect was weak. In contrast to the noncompetitive NMDA antagonist MK 801, there were no signs of CGP 40116 producing a proconvulsant response in this model. In the nonhabituated mouse, MK 801 promoted hyperlocomotion at low doses and hypolocomotion and ataxia at high doses, while CGP 40116 dose-dependently suppressed motor behaviour. Because CGP 40116 and MK 801 exert opposite effects on the seizure threshold to pilocarpine and differentially alter species-typical behaviours in the mouse, it is suggested that different populations of NMDA receptors may mediate their effects. The indivisibility of seizure suppression and motor impairment noted previously with noncompetitive NMDA antagonists such as MK 801 appears also to apply to the new generation competitive NMDA antagonist CGP 40116.

Topics: 2-Amino-5-phosphonovalerate; Animals; Dizocilpine Maleate; Grooming; Limbic System; Locomotion; Male; Mice; Mice, Inbred Strains; Motor Activity; Pilocarpine; Receptors, N-Methyl-D-Aspartate; Seizures

1. The competitive antagonists at the N-methyl-D-aspartate (NMDA) receptor, CGP39551 and CGP37849, protected against the barbiturate withdrawal syndrome in mice, as measured by ratings of convulsive behaviour on handling. 2. The effective doses of these compounds were lower than those required to prevent seizures due to NMDA in naive animals; these were in turn lower than those needed to prevent the convulsive effects of the alpha-aminobutyric acid (GABA) antagonist, bicuculline. 3. The NMDA-receptor antagonists did not alter the increase in the incidence of convulsions due to the GABAA antagonist, bicuculline, that is seen during barbiturate withdrawal, although the latencies to these convulsions during barbital withdrawal were significantly increased after CGP39551. 4. Barbiturate withdrawal did not affect the convulsive actions of NMDA, whether measured by the incidence of convulsions or by intravenous infusion. 5. The Bmax for [3H]-dizocilpine ([3H]-MK801) binding was significantly increased by chronic barbital treatment in cerebrocortical but not in hippocampal tissues, while the Kd remained unaltered in either case. 6. At 1 h and 24 h after administration of a single dose of barbitone, the Bmax for [3H]-dizocilpine binding was unaltered in cerebrocortical tissue. Acute addition of barbitone in vitro did not alter [3H]-dizocilpine binding or the displacement of binding of thienylcyclohexylpyridine.

Topics: 2-Amino-5-phosphonovalerate; Animals; Barbital; Bicuculline; Cerebral Cortex; Dizocilpine Maleate; Hippocampus; Male; Mice; Motor Activity; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Seizures; Substance Withdrawal Syndrome

Generalized barrel-rolling convulsions and focal hypermetabolic responses in the cerebellar cortex of conscious rats to lateral ventricular injection of the neuropeptide, endothelin-1 (ET; 9 pmol), were diminished or eliminated by i.c.v. pretreatment with the glutamatergic NMDA receptor antagonist, MK-801 (44 nmol). Using the quantitative autoradiographic [14C]deoxyglucose technique, we assessed rates of glucose metabolism in individual structures anatomically connecting forebrain nuclei within a polysynaptic network linked to the cerebellar cortex. Cerebellar cortical afferent sources from specific subnuclei of the inferior olivary complex, cuneate nucleus, and medial vestibular nucleus, all of which were hypermetabolic following injection of ET alone, were also inhibited by MK-801. The findings indicate that a convulsive i.c.v. dose of ET elicits an NMDA-related stimulatory effect, whose origin is probably at the periventricular caudate nucleus, that activates rates of glucose metabolism in several afferent sources and subregions of the cerebellar cortex involved in the regulation of equilibrium, posture, and the visuovestibular system.

Topics: Animals; Behavior, Animal; Biotransformation; Body Temperature; Cerebellar Cortex; Deoxyglucose; Dizocilpine Maleate; Endothelins; Glucose; In Vitro Techniques; Injections, Intraventricular; Male; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

Systemic administration of kainic acid in the rat results in the development of a characteristic excitotoxic syndrome, consisting of automatisms (wet dog shakes, WDS), sustained limbic seizures and brain damage. Since kainate increases the release of excitatory amino acid neurotransmitters such as glutamate, this syndrome is thought to be due, at least in part, to excessive activation of glutamate receptors, particularly of the N-methyl-D-aspartate (NMDA) subtype. We examined the effect of D-cycloserine, a partial agonist for the NMDA receptor-associated glycine binding site, in the kainate model of limbic seizures in rats. For comparison, the uncompetitive NMDA antagonist MK-801 (dizocilpine) and the GABAmimetic anticonvulsant diazepam were used. D-Cycloserine exerted a potent, dose-dependent and long-lasting anticonvulsant effect against kainate-induced seizures. At 160 mg/kg, seizures were almost completely suppressed by D-cycloserine over a 3 h observation period. No adverse effects were observed at anticonvulsant doses of D-cycloserine. In contrast to its potent effect on kainate-induced seizures, D-cycloserine did not significantly alter the number of automatisms (WDS) determined after kainate. MK-801, 0.3 mg/kg, also markedly reduced seizure severity in response to kainate, but this anticonvulsant effect was accompanied by marked motor impairment. Similarly, diazepam, 5 mg/kg, significantly attenuated kainate-induced seizures but marked ataxia was observed at this dosage. In contrast to D-cycloserine, both MK-801 and diazepam reduced WDS behaviour caused by kainate. The data demonstrate that pharmacological manipulation of the strychnine-insensitive glycine site is a powerful means of protecting against kainate-induced seizures.

Topics: Animals; Behavior, Animal; Cycloserine; Diazepam; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Kainic Acid; Rats; Rats, Wistar; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Seizures; Strychnine

Injection of large doses of ammonia into rats leads to depletion of brain ATP. However, the molecular mechanism leading to ATP depletion is not clear. The aim of the present work was to assess whether ammonium-induced depletion of ATP is mediated by activation of the NMDA receptor. It is shown that injection of MK-801, an antagonist of the NMDA receptor, prevented ammonia-induced ATP depletion but did not prevent changes in glutamine, glutamate, glycogen, glucose, and ketone bodies. Ammonia injection increased Na+,K(+)-ATPase activity by 76%. This increase was also prevented by previous injection of MK-801. The molecular mechanism leading to activation of the ATPase was further studied. Na+,K(+)-ATPase activity in samples from ammonia-injected rats was normalized by "in vitro" incubation with phorbol 12-myristate 13-acetate, an activator of protein kinase C. The results obtained suggest that ammonia-induced ATP depletion is mediated by activation of the NMDA receptor, which results in decreased protein kinase C-mediated phosphorylation of Na+,K(+)-ATPase and, therefore, increased activity of the ATPase and increased consumption of ATP.

Topics: Acetates; Adenosine Triphosphate; Ammonia; Animals; Brain; Bronchial Spasm; Dizocilpine Maleate; Enzyme Activation; Glutamine; Hyperventilation; Male; Neurons; Phosphorylation; Protein Kinase C; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Sodium-Potassium-Exchanging ATPase

The mRNA levels of four immediate early genes (IEG) were measured in rat brain regions 60 min after administration of pilocarpine (30 mg/kg) to lithium-treated (3 mmol/kg) rats, during generalized convulsive status epilepticus. Northern blots demonstrated induction of the genes in the order of c-fos = jun-B > c-jun > jun-D with large increases in the cerebral cortex, hippocampus, and striatum, a smaller increase in the cerebellum, and less in the brainstem. The mRNA levels of these four IEG were measured in rat cerebral cortex and hippocampus at several times after administration of the cholinergic agonist pilocarpine (5 or 30 mg/kg) with or without lithium pretreatment (3 mmol/kg, 16 h prior, or chronic 4 week dietary administration). Treatment with pilocarpine (30 mg/kg) alone increased mRNA levels in the order of c-fos > jun-B > c-jun but did not change the jun-D mRNA level, and maximal c-fos and jun-B mRNA levels occurred earlier (30 min) in the cortex than in the hippocampus. Treatment with the lower dose of pilocarpine (5 mg/kg) alone caused only small increases in c-fos and jun-B mRNA levels and these responses were unaffected by lithium pretreatment. Lithium pretreatment potentiated IEG expression induced by 30 mg/kg pilocarpine, likely as a result of the seizures caused by this combination of drugs because pretreatment with anticonvulsants (diazepam or MK-801) blocked seizures and the enhanced IEG mRNA levels. The mRNA levels were increased during seizures in the order of c-fos > jun-B > c-jun > jun-D in the hippocampus and jun-B > c-fos > c-jun > jun-D in the cortex, and were increased for a longer duration as well as to a greater extent than after administration of pilocarpine alone. Administration of pilocarpine (30 mg/kg) to rats treated chronically with lithium caused increases similar to those measured with acute lithium pretreatment. Thus the induction of IEG by cholinergic stimulation varied with dose, time, and brain region, and unique responses were observed for each of the IEG. Lithium pretreatment did not impair IEG expression induced by the lower dose of pilocarpine and greatly enhanced expression of IEG after administration of the higher dose of pilocarpine concomitant with seizure activity.

Topics: Animals; Cerebral Cortex; Diazepam; Dizocilpine Maleate; Hippocampus; Lithium; Male; Pilocarpine; Rats; Rats, Sprague-Dawley; Seizures; Transcription, Genetic

The behavioral changes associated with seizures induced by auditory stimulation in magnesium (Mg)-deficient rats originate in deep brain structures and secondarily project to neocortex. In the present study, we examined the roles of N-methyl-D-aspartate (NMDA) receptors in this seizure model. The intraperitoneal administration of the competitive NMDA receptor blocker DL-2-amino-7-phosphonoheptanoic acid (36 and 72 mg/kg) and the non-competitive NMDA receptor blocker MK-801 (1.35 and 2.7 mg/kg), completely prevented the induction of seizure and bradyarrhythmia or sudden death resulting from seizure. Therefore, the white-noise-induced seizures in Mg-deficient rats are linked to increased neuronal excitability via the NMDA receptor.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Anticonvulsants; Body Weight; Dizocilpine Maleate; Electrocardiography; Electroencephalography; Electrolytes; Magnesium Deficiency; Male; Noise; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

Both the antiepileptic, carbamazepine, and the N-methyl-D-aspartate receptor antagonist, dizocilpine, have shown preclinical efficacy against behavioral and toxic effects of cocaine. Nonetheless, side effects or toxicity of these compounds either alone or in conjunction with cocaine are problematic. 5-Aminocarbonyl-10,11-dihydro-5h-dibenzo[a,d]cyclohepten-5,1 0-imine (ADCI), a molecular hybrid of these compounds, has been shown to have a broad anticonvulsant profile with a good protective index (behavioral TD50/anticonvulsant ED50). In male Swiss Webster mice, ADCI and dizocilpine produced dose-dependent protection against the convulsant effects of cocaine that were insensitive to carbamazepine. However, in contrast to dizocilpine, ADCI did not produce behavioral impairment on the inverted screen test demonstrating a protective index of greater than 15; the protective index for dizocilpine was 1.2. All three compounds attenuated the locomotor stimulant effects of cocaine without significantly decreasing locomotor activity on their own, although the cocaine antagonism was not always dose dependent. Only dizocilpine increased spontaneous locomotor activity when given alone and augmented the locomotor stimulant effects of cocaine. The results confirm the novel anticonvulsant activity of ADCI and its lack of phencyclidine-like behavioral side effects. The data also suggest a modest blocking action of these compounds against the locomotor stimulatory effects of cocaine.

Topics: Animals; Anticonvulsants; Carbamazepine; Cocaine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Male; Mice; Motor Activity; Receptors, N-Methyl-D-Aspartate; Seizures; Substance-Related Disorders

Glial cell line-derived neurotrophic factor (GDNF) is a novel member of the transforming growth factor-beta superfamily with potent trophic effects on dopamine neurons. Kainate-induced epileptic seizures have been shown to induce gene expression of trophic factors, particularly members of neurotrophin or fibroblast growth factor families, in the hippocampus. In this study, we examined the effects of kainate (12 mg/kg, i.p.)-induced epileptic seizures on the expression of the novel neurotrophic factor GDNF in the hippocampus. While GDNF messenger RNA was not detected during development or in normal adult rats in the hippocampus, kainate-induced epileptic seizures markedly increased GDNF messenger RNA in scattered neurons in the dentate granule layer 3 h after injection. Six hours after kainate almost all dentate granule cells and expressed GDNF messenger RNA. The increase in GDNF messenger RNA in the dentate granule layer returned almost to control levels 24 h after kainate; however, there was still expression of GDNF messenger RNA in the hilus/CA4 and also in pyramidal neurons in areas CA1-CA3. We conclude that GDNF messenger RNA is regulated, in part, via glutamate-mediated excitation and may play a role in long-lasting structural and/or functional reorganization in the hippocampal formation.

Topics: Animals; Base Sequence; Dizocilpine Maleate; Dopamine; Female; Gene Expression Regulation; Glial Cell Line-Derived Neurotrophic Factor; Hippocampus; Kainic Acid; Male; Molecular Sequence Data; Nerve Growth Factors; Nerve Tissue Proteins; Neurons; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures

Acute treatment of mice with D-cycloserine (a high efficacy, partial agonist at strychnine-insensitive glycine receptors) resulted in dose- and time-dependent increases in the threshold for electrically induced tonic seizures. This anticonvulsant effect was observed at doses which did not induce motor impairment, as determined by the rotarod test. Despite the relatively high intrinsic efficacy of D-cycloserine at glycine receptors, this drug did not produce proconvulsant effects in mice at any of the doses (5-320 mg/kg) or time points examined. Prolonged treatment with D-cycloserine led to a reduction of its anticonvulsant effect. Similar to D-cycloserine, the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (dizocilpine), dose dependently increased the electroconvulsive threshold. Combined treatment with MK-801 and D-cycloserine led to significant anticonvulsant effects, but these effects were simply additive and not synergistic. In contrast to anticonvulsant activity, the motor impairing effect of MK-801 was markedly potentiated by D-cycloserine. The data substantiate that high efficacy glycine/NMDA receptor partial agonists such as D-cycloserine exert anticonvulsant activity at non-toxic doses. The finding that motor impairing but not anticonvulsant effects of MK-801 were potentiated by D-cycloserine suggests that different pharmacodynamic actions of NMDA receptor antagonists are differentially modulated by the glycine receptor, which could be related to the regional heterogeneity of the NMDA receptor complex in the brain.

Topics: Animals; Anticonvulsants; Brain; Cycloserine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Male; Mice; Mice, Inbred Strains; Motor Activity; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Seizures

Seizures may be induced in mice in response to stimulation of subtypes of glutamate receptors by kainic acid or inhibition of certain voltage-dependent potassium channels by 4-aminopyridine (4-AP). The anti-seizure efficacy of intraperitoneally administered anticonvulsants and Ca++ antagonists to CF-1 mice was tested using these models. The order of potency for prevention of kainate convulsions and the subsequent lethality was: dihydropyridine Ca++ antagonists (nicardipine, nisoldipine > nitrendipine > nifedipine > nimodipine) followed by verapamil > prenylamine > diltiazem > flunarizine > remacemide HCl > ethosuximide > valproate. In the 4-AP model the order of potency to prevent hind limb tonic extension was: MK801(+/-) > lamotrigine > phenytoin, phenobarbital > carbamazepine > FPL 12495AA (the desglycine metabolite of remacemide HCl), remacemide HCl > flunarizine > prenylamine >>> valproate. Therefore, compounds that limit activation of kainate receptors and voltage-operated linked calcium channels are active in the kainate model. Agents effective against maximal electroshock appear to be effective in the 4-AP model.

Topics: 4-Aminopyridine; Animals; Anticonvulsants; Calcium Channel Blockers; Dizocilpine Maleate; Ion Channel Gating; Kainic Acid; Male; Mice; Seizures

Quisqualate (Quis) and other excitotoxins such as ibotenate and N-methyl aspartate, have been used to destroy neurons in the area of the nucleus basalis magnocellularis (NBM) in order to study the relationship between loss of cholinergic neurons in the basal forebrain and various behavioral deficits, including learning and memory impairments. The results of several studies suggest that although Quis NBM lesions may produce greater depletions in cortical choline acetyltransferase levels than ibotenate lesions, the learning/memory deficits tend to be milder following Quis lesions. In these studies, it was often assumed that the lesions induced by Quis were restricted to the local vicinity of the injection. However, in the present study, we found that an injection of Quis into the NBM/substantia inominata (SI) region often induces limbic seizures and disseminated brain damage. Specifically, we found that an injection of Quis into the NBM/SI area of female rats at a dose (120 nmol) used by others in previous behavioral studies produced massive damage in areas distant from the lesion site, particularly in the amygdala and piriform cortex. This disseminated damage occurred in 50% of the rats treated with Quis, was typically more severe than damage at the injection site, and was often accompanied by equally severe "mirror" lesions in the contralateral amygdala and piriform cortex. Injecting rats with MK-801 (1 mg/kg) 30 min before the Quis injection protected against the disseminated damage. These data underscore the need for careful histological evaluation of excitotoxic lesions and for caution in interpreting the relationship between altered transmitter markers and learning/memory impairment seen following these lesions.

Topics: Amygdala; Animals; Brain Damage, Chronic; Dizocilpine Maleate; Female; Limbic System; Motor Activity; Quisqualic Acid; Rats; Rats, Sprague-Dawley; Seizures; Stereotaxic Techniques; Substantia Innominata

Microinjection of high doses of morphine into the spinal lumbar intrathecal (i.t.) space of mice produces dose-dependent clonic seizure-like excitatory effects. Naloxone, an opioid antagonist (10 mg/kg, i.p.), injected 5 min prior to i.t. morphine, did not reverse the seizure-like motor effects, suggesting that these effects of morphine are not mediated through opioid receptors. Systemic administration of MK-801, a non-competitive NMDA receptor antagonist (0.01-0.10 mg/kg, i.p.), or ACEA-1011, a novel NMDA receptor/glycine site antagonist (0.5-20.0 mg/kg, i.p.), attenuated the clonic seizure-like excitatory effects induced by i.t. morphine in a dose-dependent manner. Sensorimotor performance of the mice was evaluated using the rotarod test. Although both compounds (MK-801 and ACEA-1011) impaired the sensorimotor performance of mice in a dose-dependent fashion, there was no impairment of motor performance at doses employed to block the excitatory effects induced by i.t. morphine. These data suggest that NMDA receptors play a pivotal role in the clonic seizure-like behaviors induced by i.t. morphine.

Topics: Analgesics; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; In Vitro Techniques; Injections, Intraperitoneal; Injections, Spinal; Male; Mice; Morphine; Motor Activity; Oocytes; Quinoxalines; Receptors, N-Methyl-D-Aspartate; Seizures; Xenopus laevis

The role of N-methyl-D-aspartate (NMDA) in the development and expression of kindled seizures was assessed using a crossover design. Rats were stimulated once daily in the perforant path for 10 consecutive days 30 min following daily administration of saline or the NMDA antagonist MK-801 (1.0 mg/kg) (phase I). Five to 10 days elapsed prior to an additional 10 stimulations with the drug treatments reversed (phase II). A separate group of animals was stimulated following saline administration in both phases of the study. MK-801 produced a significant increase in afterdischarge (AD) threshold and a suppression of behavioral seizure development during the first 10 stimulations. However, upon removal of the drug, an immediate increase in seizure stage and the number of animals displaying generalized seizure signs (clonic component) was observed. Paradoxically, MK-801 also produced an increase in mean AD duration in the perforant path and dentate gyrus over the first 10 stimulations. Upon reversal of the dose treatments in phase II of the study, AD duration increased in animals treated with MK-801 for the first time, and decreased in animals taken off MK-801 and stimulated drug free. The augmentation in AD associated with MK-801 was partially attributed to an increase in secondary or rebound AD. Rebound ADs occurred more frequently, had a decreased latency and longer duration in drugged compared to control animals, irrespective of the phase of the study. These data indicate that MK-801 possesses anticonvulsant properties with respect to behavioral seizure, and is less effective as an antiepileptogenic agent-i.e., significant kindling development occurred with MK-801 in the absence of overt behavioral expression of the kindled response. A dissociation between seizure stage and AD duration suggests that independent mechanisms may control the electrographic and behavioral indices of kindling.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Electric Stimulation; Electroencephalography; Electrophysiology; Evoked Potentials; Kindling, Neurologic; Male; Rats; Receptors, N-Methyl-D-Aspartate; Seizures

Mice selectively bred to be Withdrawal Seizure-Prone (WSP) or Seizure-Resistant (WSR) after chronic ethanol administration have been reported to be differentially sensitive to the anticonvulsant and proconvulsant effects on alcohol withdrawal of drugs interacting with glutamate receptors. Several behavioral effects of the noncompetitive glutamate receptor antagonist, dizocilpine, were determined in WSP and WSR mice to see whether their differential sensitivity generalized to effects unrelated to seizures, and to see whether it was only apparent during ethanol withdrawal. Dizocilpine potentiated the loss of righting reflex induced by ethanol, and dose-dependently stimulated habituated and nonhabituated open field activity. WSP and WSR mice were equally sensitive to these effects of dizocilpine. Pretreatment with dizocilpine increased the transcorneal amperage necessary to produce maximal electroshock seizures: WSR mice were more sensitive than WSP to this effect. Ethanol withdrawal (i.e., testing 6 h after a 24-h exposure to ethanol vapor) and dizocilpine had several effects on mice tested in the hole-in-wall apparatus. Several differences between WSP and WSR mice were also found, but in no case did dizocilpine differentially affect ethanol-withdrawing WSP and WSR mice. Across these experiments, differences between WSP and WSR mice in response to dizocilpine were rather specific. For some responses, WSP and WSR mice were equally sensitive, but only in the seizure-related measure assessed were naive WSR mice more sensitive than WSP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anticonvulsants; Convulsants; Dizocilpine Maleate; Electroshock; Ethanol; Exploratory Behavior; Female; Male; Mice; Mice, Inbred Strains; Motor Activity; Postural Balance; Seizures; Substance Withdrawal Syndrome

The present experiments examined whether pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, MK-801 and dextrorphan, could antagonize cocaine-induced convulsions and lethality in conscious Sprague-Dawley (SD) rats and whether urethane anesthesia alters the observed interactions. Conscious, restrained male SD rats received continuous i.v. infusions of cocaine hydrochloride (1.25 mg/kg.min) until convulsions and death occurred. Cocaine doses of 21.2 +/- 1.8 and 29.5 +/- 2.5 mg/kg caused convulsions and death, respectively, in saline treated rats (n = 8). Convulsions were absent in MK-801 (1 mg/kg, i.v.; n = 8) pretreated rats; the lethal cocaine dose was 44.0 +/- 2.7 mg/kg (p < 0.05). In contrast, urethane anesthesia (1.2 g/kg, i.p.) decreased the dose of cocaine required to cause toxicity, compared to that in saline controls (24.8 +/- 0.8 mg/kg, n = 13), in MK-801 (2.0 +/- 0.3, n = 7; p < 0.01) and in dextrorphan mg/kg, n = 13), in MK-801 (2.0 +/- 0.3, n = 7; p < 0.01) and in dextrorphan (25 mg/kg, i.v.; 13.1 +/- 1.4, n = 6; p < 0.01) pretreated rats. Pressor responses with little change in heart rate were evident during cocaine infusion in vehicle pretreated rats. Bradycardiac responses were noted to cocaine in groups following NMDA receptor blockade. Reversal of the pressor response to cocaine was noted in MK-801 pretreated animals, while dextrorphan pretreatment moderated cocaine-induced increases in blood pressure. Ventilatory support protected against cocaine lethality in urethane anesthetized rats, indicating that respiratory failure is the proximate cause of death with cocaine infusion. However, artificially ventilated rats, pretreated with MK-801, were more sensitive (lethal cocaine dose, 76.6 +/- 8.0 mg/kg, n = 5) than vehicle pretreated rats (129.4 +/- 15.8 mg/kg, n = 6), indicating that MK-801 may increase both the respiratory and the cardiac toxicity of cocaine in urethane anesthetized rats. Interactions between NMDA receptors and cocaine are modified by urethane anesthesia.

Topics: Anesthesia; Animals; Blood Pressure; Body Temperature; Cocaine; Consciousness; Dextrorphan; Dizocilpine Maleate; Drug Interactions; Heart Rate; Injections, Intravenous; Male; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Respiration Disorders; Seizures; Urethane

Recent studies have shown that alterations in gamma-aminobutyric acid (GABAA) and N-methyl-D-aspartate (NMDA) receptor subunit mRNA levels are associated with the effects of chronic ethanol exposure as well as genetic selection for ethanol withdrawal seizure sensitivity. We have previously shown that chronic ethanol exposure in rats results in a decrease in the levels of GABAA receptor alpha 1 and alpha 2 subunit mRNAs in cerebral cortex, an increase in the levels of alpha 6 subunit mRNAs in cerebellum and no alteration in alpha 3, GAD, ribosomal RNA or polyA + RNA levels in these regions. Since chronic ethanol administration increases the expression of [3H]Ro15-4513 binding sites in cortex and cerebellum with no effect on other GABAA receptor recognition sites, we hypothesized that the expression of other subunits would be altered in these regions. In addition, since ethanol appears to interact with zolpidem-sensitive GABAA receptors in rat brain, we investigated the effect of chronic ethanol administration on these recognition sites. Chronic ethanol administration increased [3H]zolpidem binding with no effect on levels of GABAA receptor beta 2 and gamma 2 subunit mRNAs. In addition, we examined the levels of NMDAR1 receptor subunit mRNAs since chronic ethanol administration results in increased levels of [3H]MK-801 recognition sites on NMDA receptors. NMDAR1 receptor subunit mRNAs were not altered following chronic ethanol exposure in rat cortex or hippocampus. These studies underscore the specificity of ethanol interactions with these receptors and the importance of understanding the mechanisms of both GABAA and NMDA receptor regulation in elucidating the etiology of ethanol dependence.

Topics: Alcoholism; Animals; Azides; Base Sequence; Benzodiazepines; Cerebellum; Cerebral Cortex; Dizocilpine Maleate; DNA, Complementary; Gene Expression; Hippocampus; Male; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Seizures; Substance Withdrawal Syndrome; Zolpidem

Repeated administration of cocaine (45 mg/kg/day) for 7 days to Swiss-Webster mice resulted in a progressive increase in the convulsive response to cocaine and augmentation in lethality rate. Pretreatment with the nitric oxide (NO) synthase inhibitors, L-NAME (100 mg/kg/day) or NO-Arg (25 mg/kg/day), prior to cocaine administration completely abolished the sensitization to the convulsive and lethal responses to cocaine. These findings suggest a role for NO in cocaine-induced toxicity.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Cocaine; Dizocilpine Maleate; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Receptors, Phencyclidine; Seizures

Intracerebroventricular (i.c.v.) infusion in mice of the selective metabotropic excitatory amino acid receptor agonist 1S,3R-1- aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) (0.6-575 nmol/min) dose dependently induced face washing and scratching. In contrast, the subtype-specific ionotropic excitatory amino acid receptor agonists N-methyl-D-aspartate (NMDA), kainate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) (0.3-3.0 nmol/min) dose dependently induced clonic convulsions. I.c.v. infusion of the non-selective metabotropic receptor agonists ibotenate (6 nmol/min) or quisqualate (30 nmol/min) induced clonic convulsions. However, when ionotropic receptors were blocked with (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine maleate (MK-801, dizoclipine) (3 nmol/min) or 2,3-dihydroxy-6-nitro-7- sulfamoyl-benzo(f)-quinoxaline (NBQX) (9 nmol/min), respectively, face washing and scratching behavior emerged. Neither MK-801 or NBQX (ED50 value > 100 nmol/min), nor the putative metabotropic receptor antagonist L-amino-3-phosphoro-propionic acid (L-AP3) (> 176 nmol/min); nor the dopamine receptor antagonists SCH 23390 (> 74 nmol/min), metoclopramide (> 89 nmol/min) and haloperidol (> 27 nmol/min) antagonized 1S,3R-ACPD-induced scratching (144 nmol/min). These results suggest that the behavioral consequences of i.c.v. infusion of 1S,3R-ACPD in mice reflect a selective activation of metabotropic receptors that differs from the behavioral changes observed with i.c.v. infusion of ionotropic receptor agonists.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Behavior, Animal; Cycloleucine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ibotenic Acid; Kainic Acid; Male; Mice; N-Methylaspartate; Quinoxalines; Quisqualic Acid; Receptors, Glutamate; Seizures

Immunoblot analysis using a phosphotyrosine-specific antibody was performed to investigate tyrosine phosphorylation of the mitogen activated protein (MAP) kinase in the rat brain. Epileptic seizures induced by systemic injection of bicuculline caused a rapid and transient stimulation of MAP kinase tyrosine phosphorylation in hippocampus and somatosensory cortex. This increase in tyrosine phosphorylation was markedly attenuated by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. In contrast, in the cerebellum, tyrosine phosphorylation of MAP kinase remained undetectable after bicuculline-induced seizures. These results demonstrate that generalized seizures stimulate tyrosine phosphorylation of MAP kinase in a regionally selective manner.

Topics: Animals; Bicuculline; Brain; Brain Ischemia; Dizocilpine Maleate; Enzyme Activation; Hippocampus; Immunoblotting; Mitogens; Phosphorylation; Phosphotyrosine; Protein-Tyrosine Kinases; Rats; Rats, Inbred Strains; Seizures; Somatosensory Cortex; Tyrosine

Administration to mice of N-methyl-DL-aspartate (NMDLA; 680-3400 mumol/kg IP) produced a behavioural syndrome of scratching, running, pawing, clonus, loss of righting and tonic convulsions. Measures of latency to appearance of the behaviours and percentage of animals displaying the behaviour (frequency) indicated that the latency to appearance of running behaviour, clonus and tonic convulsions were all dose dependant. Chlormethiazole (155-622 mumol/kg IP) given 15 min before NMDLA (3400 mumol/kg) dose-dependently inhibited all the behaviours, increasing the latency to appearance of scratching, running and clonus and reducing the incidence of pawing, loss of righting and tonic convulsions. Tonic seizures induced by NMDLA (3400 mumol/kg) were inhibited by the following drugs (ED50 values in mumol/kg in brackets): chlormethiazole (210); pentobarbitone (67); dizocilpine (0.9). The diazepam value (38) was estimated as complete inhibition was not obtained. Chlormethiazole (1 mM) did not affect the binding of [3H]-dizocilpine to rat cortical membranes or the stimulation of this binding by glutamate (10 microM), glycine (10 microM) or spermidine (100 microM). It is therefore concluded that whilst chlormethiazole effectively antagonises the convulsive behavioural syndrome induced by injection of NMDLA, it does not do so by interacting with the NMDA receptor complex but more probably by its known interaction with the GABAA receptor complex.

Topics: Animals; Behavior, Animal; Cerebral Cortex; Chlormethiazole; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Membranes; Mice; Mice, Inbred Strains; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Seizures

An assortment of glutamate antagonists with differing selectivities for NMDA and AMPA-type glutamate receptors, were tested for their effects in the mouse pilocarpine model of complex partial seizures. MK 801 (0.1-0.8 mg/kg) and high doses of HA 966 (50 mg/kg) were proconvulsant, whilst CGP 40116 (1-8 mg/kg) and low doses of HA 966 (0.4-10 mg/kg) inhibited pilocarpine-induced convulsions. CPP (5-20 mg/kg) and NBQX (1-50 mg/kg) were without effect. The dopamine D1 agonist SKF 38393 (10 mg/kg) facilitated the convulsant effects of low-dose pilocarpine (100 mg/kg). MK 801 (0.1-0.2 mg/kg) and HA 966 (50 mg/kg) interacted synergistically with SKF 38393 to promote the proconvulsant effects of D1 stimulation, whilst CPP (10-20 mg/kg) and HA 966 (10 mg/kg) had the opposite effect. CGP 40116 and NBQX were without effect. These results show that the convulsant qualities of MK 801 and SKF 38393, that have been detected in animal models of Parkinson's disease, can be reproduced in the pilocarpine model of epilepsy. Whilst the glutamate antagonists all interact synergistically with SKF 38393 to improve its antiparkinson activity, only MK 801 and high doses of HA 966 similarly potentiate the convulsions associated with D1 stimulation. An appropriate mixture of a glutamate antagonist and a D1 agonist could theoretically be used beneficially in the treatment of Parkinson's disease, without causing epilepsy as a side effect.

Topics: 2-Amino-5-phosphonovalerate; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Dizocilpine Maleate; Dopamine Agents; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Mice; Mice, Inbred Strains; Pilocarpine; Piperazines; Pyrrolidinones; Quinoxalines; Receptors, AMPA; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate; Seizures

We have studied the effect of two glutamate receptor antagonists on seizures and hippocampal neurone loss in the rat after systemic kainic acid administration. Intraperitoneal injection of the novel AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid) receptor antagonist NBQX (6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione) (30 mg/kg x 3 and 15 mg/kg x 3) administered 30 and 15 min. before and simultaneously with injection of kainic acid (5 mg/kg) intraperitoneally, dramatically enhanced the toxicity of kainic acid leading to death of all animals. When the NBQX dose was reduced to 8 mg/kg x 3, all animals survived and neurone damage in the hippocampus did not differ from control animals. When NBQX (30 mg/kg x 3) was administered 30- or 60 min after injection of kainic acid (8 mg/kg) intraperitoneally, no changes were observed concerning survival rates, seizure generation and neurone loss. Post-kainic acid treatment with the non-competitive NMDA receptor antagonist MK-801 (0.5 mg/kg and 1.0 mg/kg), 30 and 60 min. after intraperitoneally injection of kainic acid 8 mg/kg, abolished seizures in all animals and the neurone damage in the hippocampus was completely prevented. The results emphasize the importance of the NMDA-receptor activation for seizure generation and subsequent brain damage after intraperitoneally kainic acid. The paradoxical, unexpected effects of NBQX contrast to the protective effect of this compound after cerebral ischaemia and hypoglycaemia, conditions which are also characterized by glutamate-mediated damage. One possible explanation of the lowered seizure threshold to kainic acid after NBQX could be that NBQX is blocking AMPA receptors on interneurones more efficiently than on pyramidal cells.

Topics: Animals; Behavior, Animal; Brain; Dizocilpine Maleate; Drug Synergism; Kainic Acid; Male; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Seizures; Survival Rate

Through the genetic technique of selective breeding, a mouse line [Withdrawal Seizure Prone (WSP)] has been developed that expresses severe handling-induced convulsions (HIC) after cessation of chronic ethanol exposure. These mice also display rebound elevations in HIC after a single ethanol injection. In the current studies, we tested WSP mice in several paradigms. WSP mice were found to be marginally sensitive to the effects of acute doses of dizocilpine to reduce HIC. However, when tested during acute withdrawal from a single ethanol injection, WSP were more sensitive to this compound. Although N-methyl-D-aspartate significantly elevated HIC in naive WSP mice, it was more effective at low doses when given during acute withdrawal. Withdrawing mice were slightly more sensitive than naive mice to kainic acid. Pentylenetetrazole elevated HIC in naive and withdrawing mice; it was marginally more effective in naive mice. Diazepam inhibited HIC in both naive and withdrawing mice, and was slightly more effective during acute withdrawal. This pattern of results suggests that acute alcohol withdrawal is accompanied by altered sensitivity to convulsants and anticonvulsants. These changes include enhanced sensitivity in at least two excitatory amino acid-gated ion channel binding sites.

Topics: Alcohol Withdrawal Delirium; Animals; Anticonvulsants; Arousal; Convulsants; Diazepam; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Handling, Psychological; Kainic Acid; Mice; Mice, Inbred Strains; N-Methylaspartate; Pentylenetetrazole; Receptors, N-Methyl-D-Aspartate; Seizures

The current study measured extracellular fluid (ECF) levels of excitatory amino acids before and during the onset of thiamine deficiency-induced pathologic lesions. Male Sprague-Dawley rats were treated with daily pyrithiamine (0.25 mg/kg i.p.) and a thiamine-deficient diet (PTD). Microdialysates were simultaneously collected from probes inserted acutely via guide cannulae into right paracentral and ventrolateral nuclei of thalamus and left hippocampus of PTD and pair-fed controls. Hourly samples were collected from unanesthetized and freely moving animals. Basal levels obtained at a prelesion stage (day 12 of PTD treatment) were unchanged from levels in pair-fed controls. In samples collected 4-5 h after onset of seizures (day 14 of PTD), the levels of glutamate were elevated an average 640% of basal levels in medial thalamus and 200% in hippocampus. Glutamine levels declined, taurine and glycine were elevated, and aspartate, GABA, and alanine were unchanged during this period. Within 7 h after seizure onset glutamine was undetectable in both areas, whereas glutamate had declined to approximately 200% in thalamus and 70% in hippocampus. No significant change in glutamate, aspartate, or other amino acids was observed in dialysates collected from probes located in undamaged dorsal-lateral regions of thalamus. Number of neurons within ventrolateral nucleus of thalamus was significantly greater in PTD animals in which the probe was dialyzed compared with nondialyzed, suggesting that removal of excitatory amino acids was protective. No significant pathologic damage was evident in hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acids; Animals; Dizocilpine Maleate; Extracellular Space; Hippocampus; Male; Microdialysis; Pyrithiamine; Rats; Rats, Sprague-Dawley; Reference Values; Seizures; Thalamus; Thiamine; Thiamine Deficiency; Time Factors

Impairment of cellular energy metabolism plays an important role in the expression of brain injury resulting from a variety of acute neurologic disorders. The role of mitochondrial energy metabolism in excitotoxic perinatal brain injury was assessed by studying the toxicity of aminooxyacetic acid (AOAA), an inhibitor of mitochondrial malate-aspartate shunt, in postnatal (PND) 7 rats. Intrastriatal injection of AOAA produced seizures and dose-dependent excitotoxic injury. The neuronal damage was attenuated by pyridoxine suggesting involvement of pyridoxal dependent mechanisms. The lesion was selectively blocked by the NMDA antagonist MK-801 but not the AMPA antagonist GYKI-52466. Furthermore, AOAA potentiated NMDA, but not AMPA or 1S,3R-ACPD, induced brain injury. The data suggest that regional impairment of cellular energy metabolism is an important determinant of selective vulnerability to excitotoxic injury in perinatal rats. Furthermore, the role of impaired energy metabolism is particularly relevant to NMDA receptor mediated brain injury.

Topics: Aminooxyacetic Acid; Animals; Animals, Newborn; Anti-Anxiety Agents; Benzodiazepines; Brain; Corpus Striatum; Dizocilpine Maleate; Hippocampus; Injections; Neurotoxins; Pyridoxine; Rats; Rats, Sprague-Dawley; Seizures; Stereotaxic Techniques

Topics: Administration, Oral; Animals; Dizocilpine Maleate; Hippocampus; Male; Neurons; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Seizures; Spermine; Trimethyltin Compounds

The KROX-20 protein (also termed EGR-2) is encoded by an immediate early gene cloned by cross-hybridization to the Drosophila melanogaster Krüppel gene. It belongs to a class of transcription factors with zinc finger motifs and binding activity to a transcriptional regulatory DNA element termed the early growth response consensus sequence. In the present study the temporospatial expression of KROX-20 was investigated in the central and peripheral nervous systems of normal rats and after various stimuli known to induce immediate early genes, including epileptic seizures, axotomy, pharmacological treatment with glutamate and alpha-adrenergic receptor antagonists, and peripheral noxious stimulation. Immunocytochemistry was performed with a specific polyclonal antiserum generated against a fusion protein containing KROX-20 sequences. In the central nervous system, KROX-20 protein demonstrated distinct constitutive nuclear expression in specific neuronal subpopulations of the cortex, septum, amygdala, olfactory bulb and hypothalamus. In addition, distinct cytoplasmic immunoreactivity was present in spinal and medullary motoneurons, dorsal root ganglion neurons and a few neuronal cell populations of midbrain and forebrain. In the CNS, KROX-20 was only induced by bicuculline-induced epileptic seizures. Topographically, the postictal increase of KROX-20 levels was restricted to areas with constitutive expression, such as cerebral cortex, fornix and amygdala. Induction of KROX-20 peaked at 4-8 h after onset of seizure activity. No increase in immunoreactivity was observed in the hippocampus, the brain region most severely affected by bicuculline-induced seizures. Transection of central and peripheral nerve fibers did not result in KROX-20 induction in axotomized neurons. However, KROX-20 was induced in Schwann-like cells after transection of the sciatic nerve. In contrast to KROX-20, KROX-24, a related transcription factor of the zinc finger family, was markedly induced in hippocampal and spinal neurons following seizures and peripheral noxious stimulation, respectively, as well as in CNS neurons following axotomy. Our data indicate that KROX-20 represents an immediately early gene product with basal expression in selected neuronal populations of the nervous system and a restricted inducibility after intentional stimuli.

Topics: Animals; Bicuculline; Central Nervous System; Denervation; Dizocilpine Maleate; DNA-Binding Proteins; Early Growth Response Protein 2; Formaldehyde; Gene Expression; Genes, Immediate-Early; Imidazoles; Male; Peripheral Nerves; Rats; Rats, Sprague-Dawley; Seizures; Tissue Distribution; Transcription Factors; Zinc Fingers

Fos, jun and krox belong to multigene families coding for transcription factors. These cellular immediate early genes (IEGs) are thought to be involved in coupling neuronal excitation to changes of target gene expression. Immunocytochemistry with specific antisera was used to assess regional levels of six IEG-encoded proteins (c-Fos, Fos B, Krox-24, c-Jun, Jun B, Jun D) in the rat forebrain after kainic acid-induced limbic seizures. The results demonstrate a complex spatial pattern of IEG induction and/or suppression in limbic and non-limbic structures. The sequence of induction within hippocampal subpopulations was identical for all IEGs investigated, following the order dentate gyrus, CA1 and CA3, and irrespective of different temporal profiles for individual transcription factors. Since Fos and Jun proteins act via homo- and heterodimer complexes at specific DNA sites, our data imply that the postictal combinatorial changes of these dimers allow a sequential and differential regulation of target gene expression in specific forebrain regions. Pretreatment with the non-competitive NMDA receptor antagonist MK-801 did not affect kainate-induced expression of IEGs in the limbic system, indicating that IEG induction in these regions is mediated by high-affinity kainate and AMPA receptors rather than NMDA receptors. In contrast, MK-801 abolished IEG induction in the somatosensory cortex and striatum, suggesting that IEG expression in non-limbic neurons occurs transsynaptically and is mediated by NMDA receptors.

Topics: Animals; Brain; Dizocilpine Maleate; DNA-Binding Proteins; Early Growth Response Protein 1; Gene Expression Regulation; Genes, Immediate-Early; Immediate-Early Proteins; Limbic System; Male; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Transcription Factors

The sensitivity of pilocarpine-induced seizures to NMDA receptor blockade with MK-801, or to inhibition of synthesis of the second messenger nitric oxide (NO) with N omega-nitro-L-arginine methyl ester (L-NAME), was studied in mice. The NO precursor L-arginine (100-500 mg/kg, IP) and L-NAME (1-125 mg/kg, IP) had no overt effects on animals' behaviour by themselves, while MK-801 (0.1-0.8 mg/kg, IP) caused motor excitability at low doses and sedation and paraplegia at high ones. Contrary to expectation, MK-801 and L-NAME failed to protect mice against limbic motor seizures induced by pilocarpine (400 mg/kg, IP), and L-arginine was not proconvulsant in mice challenged with a threshold convulsant dose of the cholinomimetic (100 mg/kg, IP). Surprisingly, both MK-801 and L-NAME were found to be proconvulsant when injected in conjunction with 100 mg/kg pilocarpine, and in both cases this convulsant action synergised with that produced by the dopamine D1 agonist SK&F38393 (10 mg/kg, IP). Concomitant administration of L-arginine (500 mg/kg) prevented the convulsant effect of 5 mg/kg L-NAME but was ineffective against 25 mg/kg L-NAME and MK-801. It is concluded that glutamate, acting through the NMDA receptor and NO production, normally suppresses epileptogenesis in the mouse pilocarpine model of limbic epilepsy.

Topics: Animals; Arginine; Dizocilpine Maleate; Drug Synergism; Male; Mice; Mice, Inbred Strains; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pilocarpine; Receptors, N-Methyl-D-Aspartate; Seizures

The objective of this study was to develop an experimental rat hippocampal seizure model based on the stimulatory effects of N-methyl-D-aspartate and to determine the inhibitory effects of MK-801 on N-methyl-D-aspartate-induced seizures.. Two separate experiments were performed. In the first experiment chemitrode-implanted rats were injected intracranially with increasing doses (5, 10, 20, and 30 micrograms) of N-methyl-D-aspartate into the hippocampus. Various electrophysiologic and behavioral parameters were examined to determine the dose required to reliably elicit hippocampal seizure activity without having toxic effects on the rats. In the second experiment rats were given an intraperitoneal injection of MK-801 (0.5 or 1 mg/kg), followed 20 minutes later by an intracranial injection of N-methyl-D-aspartate (20 or 30 micrograms). The ability of MK-801 to suppress N-methyl-D-aspartate-induced seizure activity was assessed in this experiment.. Intrahippocampal injection of 20 micrograms of N-methyl-D-aspartate produced the shortest electrical seizure latency (193 +/- 72 seconds, p < 0.01). At this dose seizure was achieved in 80% (four of five of the animals, and the highest numbers of electrical seizures per animal were produced (2.2 +/- 0.8, p < 0.05). The group that received 30 micrograms of N-methyl-D-aspartate had a shorter latency, a longer duration of behavioral seizure and a higher number of behavioral seizures (p < 0.05). However, this group suffered a 60% (three of five) mortality rate. The addition of MK-801 significantly decreased the number of seizures per animal and the total seizure duration (p < 0.05). MK-801 also reduced the latency period.. Intracranial injection of 20 micrograms of N-methyl-D-aspartate produced reliable hippocampal seizure activity without mortality. MK-801 at a dose of 1 mg/kg injected intraperitoneally had significant inhibitory effects on this seizure model.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electrophysiology; Female; Hippocampus; Injections, Intraperitoneal; Injections, Intraventricular; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

Expression of the immediate-early gene c-fos has been advanced as a marker of neuronal activity in the adult nervous system. We sought to test the validity of c-fos mRNA expression as a marker of neuronal activity during seizures and to elucidate specific neurotransmitter receptors whose activation was necessary for seizure-evoked c-fos mRNA expression. We correlated c-fos mRNA expression, measured with in situ hybridization, with kindled seizure-induced firing of hippocampal dentate granule cells or substantia nigra pars compacta and pars reticulata neurons. We found that the occurrence of seizure-evoked synchronous action potentials during the seizure exhibited a perfect qualitative correlation with the presence of c-fos mRNA expression in the granule cells 30 min following the seizure (Fisher's exact test, p = 0.002). However, there was no quantitative correlation between the number of seizure-induced population action potentials and the magnitude of c-fos mRNA expression in the granule cells. In the substantia nigra, where neuronal populations have previously been demonstrated to exhibit synchronous firing during kindled seizures, no induction of c-fos mRNA was detected in either pars compacta or pars reticulata. Pretreatment with antagonists of the NMDA subtype of glutamate receptor selectively and markedly decreased seizure-induced c-fos mRNA expression in the dentate granule cells, despite increasing the number of granule cell population action potentials. These findings illustrate the complexity of the relationship between c-fos induction and neuronal burst firing during kindled seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Dizocilpine Maleate; Electrophysiology; Excitatory Amino Acid Antagonists; Gene Expression; Genes, fos; Hippocampus; In Situ Hybridization; Kindling, Neurologic; Male; Neurons; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Seizures; Substantia Nigra

The effect of long-term treatment with ethanol was investigated on the function of gamma-aminobutyric acid A (GABAA) and N-methyl-d-aspartic acid (NMDA) receptors. Rats were rendered ethanol-dependent by repeated forced administration of a 20% ethanol solution (12 to 18 g/kg/day po) for 6 days and tested while still intoxicated or at different time intervals after withdrawal. t-[35S]Butylbicyclophosphorothionate (35S-TBPS) binding was increased by 30% in cortical homogenates of rats killed 1 to 3 hr after last ethanol administration, when compared with saline-treated animals. However, GABA-stimulated 36Cl- uptake and its enhancement by flunitrazepam was decreased in the ethanol-treated animals. 35S-TBPS binding and 36Cl- influx measured 9 to 24 hr following the last ethanol injection, when withdrawal signs were present, were unmodified with respect to saline-treated rats. Moreover, the effects of both isoniazid and FG 7142 on 35S-TBPS binding were unchanged in ethanol-dependent rats tested at 1 to 3 and 9 to 24 hr, compared with controls. In contrast, ethanol-withdrawn rats tested at 9 to 24 hr showed a dramatic enhancement in their sensitivity to the convulsant action of isoniazid (50 to 250 mg/kg, sc). The same animals were also more susceptible to the convulsant action of NMDA (0.5 to 5 micrograms/5 microliters/rat intracerebroventricularly) and kainic acid (12 mg/kg, ip), and this effect was paralleled by an enhancement (+25%) in the density of 3H-MK 801 recognition sites in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alcohol Withdrawal Delirium; Alcoholism; Animals; Brain; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Chloride Channels; Convulsants; Dizocilpine Maleate; Ethanol; Isoniazid; Kainic Acid; Male; Membrane Proteins; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Seizures; Synaptic Transmission

The role of metabotropic excitatory amino acid receptors in seizures and brain injury was examined using the selective metabotropic agonist 1S,3R-ACPD [(1S,3R)-1-aminocyclopentane-1-3-dicarboxylic acid] in 7-d-old neonatal rats. Systemic administration of 1S,3R-ACPD produced dose-dependent convulsions (ED50 = 16 mg/kg, i.p.) that were stereoselective for the active metabotropic ACPD isomer, since 1R,3S-ACPD was less potent (ED50 = 93 mg/kg, i.p.). 1S,3R-ACPD-induced seizures were antagonized by systemic administration of dantrolene, an inhibitor of intracellular calcium mobilization, but not by the ionotropic glutamate antagonists MK-801 or GYKI-52466. As indexed by hemispheric brain weight differences 5 d postinjection, unilateral intrastriatal injection of 1S,3R-ACPD (0.1-2.0 mumol/microliters), but not 1R,3S-ACPD, produced dose-dependent brain injury (maximal effect of 3.4 +/- 0.5% damage). 1S,3R-ACPD brain injury occurred in the absence of prominent behavioral convulsions. Histologic and ultrastructural examination of 1S,3R-ACPD-injected rat brains revealed swelling and degeneration of select neurons at 4 hr postinjection, but little evidence of injured neurons 5 d later. 1S,3R-ACPD-mediated brain injury was not attenuated by systemic administration of the NMDA antagonist MK-801 or the AMPA antagonist GYKI-52466. However, cointrastriatal injection of dantrolene reduced the severity of 1S,3R-ACPD injury by 88 +/- 7%. These studies indicate that seizures and neuronal injury can be elicited by the selective activation of metabotropic glutamate receptors in perinatal rats, and these effects of 1S,3R-ACPD involve the mobilization of intracellular calcium stores.

Topics: Animals; Animals, Newborn; Anti-Anxiety Agents; Benzodiazepines; Brain Injuries; Cell Nucleus; Corpus Striatum; Cycloleucine; Dantrolene; Dizocilpine Maleate; Female; Hippocampus; Male; Microscopy, Electron; Neurons; Neurotoxins; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Seizures; Stereotaxic Techniques

The role of excitatory amino acid receptors in the genesis of motor and electrocortical seizures, elicited by administration of the polyamine putrescine into the deep prepiriform cortex, has been evaluated in rats. Motor and electrocortical seizures occurred in rats receiving unilateral local injections into the deep prepiriform cortex, of putrescine (10 or 20 nmol). The selective N-methyl-D-aspartate receptor antagonist, 2-amino-7-phosphonoheptanoate (AP7), injected previously (15 min) into the deep prepiriform cortex, prevented the development of seizures induced by putrescine, injected at the same site. In addition, dizocilpine (MK-801), a non-selective NMDA antagonist or ifenprodil, a specific inhibitor of the polyamine site at the NMDA receptor, when injected into the deep prepiriform cortex, 15 min prior to putrescine, significantly protected against seizures elicited by this polyamine. A subconvulsant dose of putrescine (5 nmol) potentiated the convulsant effects of NMDA, when injected into the deep prepiriform cortex. These data indicate a potential role of polyamines in the genesis of seizures, elicited from the deep prepiriform cortex. They further suggest that activation of the polyamine site, located at excitatory amino acid NMDA receptors, within the deep prepiriform cortex, may contribute to the genesis of seizure activity in this area.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Anticonvulsants; Cerebral Cortex; Dizocilpine Maleate; Electrocardiography; Electroencephalography; Male; Putrescine; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

Excitant amino acids are implicated in audiogenic seizure (AGS) susceptibility in the genetically epilepsy-prone rat (GEPR). In the present study systemic administration of NMDA receptor antagonists significantly decreased AGS severity in the GEPR. Systemic administration of the competitive NMDA antagonists 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP) and 2-amino-7-phosphonoheptanoic acid and the non-competitive antagonist dizocilpine (MK-801) were effectively anticonvulsant in the GEPR. The inferior colliculus is the most critical nucleus for AGS initiation in the GEPR and an excitant amino acid is implicated as an important excitatory transmitter in inferior colliculus neurons. Systemically administered CPP significantly reduced inferior colliculus neuronal firing in the normal behaving rat and the GEPR concurrently with blockade of AGS and this effect occurred at nearly all sound intensities tested. Systemic administration of MK-801, while effective in blocking AGS, produced no consistent change in inferior colliculus neuronal firing, which is consistent with its very low potency in blocking AGS with bilateral microinjection into the inferior colliculus. These findings suggest that an important action of competitive, but not noncompetitive, NMDA antagonists is on brain stem auditory nuclei, especially the inferior colliculus, that are critical to AGS. MK-801 appears to exert its anticonvulsant effects in AGS network sites beyond the inferior colliculus. These findings and recent inferior colliculus slice studies suggest that NMDA receptors in inferior colliculus may have quantitatively different properties from those in other brain regions. These differences in NMDA receptor function in inferior colliculus may reflect NMDA receptor heterogeneity observed in binding studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Brain; Dizocilpine Maleate; Female; Male; N-Methylaspartate; Nerve Net; Piperazines; Rats; Seizures

MK801 is a noncompetitive blocker of N-methyl-D-aspartate receptors which has antiepileptic properties. To evaluate whether MK801 pretreatment in immature rats affects the future spontaneous recurrent seizure (SRS) rate or seizure susceptibility in a model of limbic epilepsy, MK801 (0.2 or 1.0 mg/kg, i.p.) or saline was administered to prepubescent rats 30 min prior to kainic acid (KA; 10 mg/kg, i.p.). With or without MK801 pretreatment, KA caused prolonged status epilepticus. SRS rate over the next 4 weeks, as assessed by intermittent video monitoring, was significantly lower in MK801 treated rats than in those which received KA alone. In addition, fewer MK801 treated rats (43%) developed SRS than those which got KA alone (88%). Susceptibility to generalized seizures was then tested using the volatile convulsant flurothyl; at both doses of MK801, flurothyl seizure latency was significantly greater in pretreated animals. These results show that MK801 pretreatment prior to KA induced status epilepticus reduces subsequent SRS frequency and flurothyl seizure susceptibility, while not substantially altering the acute epileptogenic effects of KA.

Topics: Animals; Cerebral Cortex; Dizocilpine Maleate; Electroencephalography; Epilepsy, Tonic-Clonic; Flurothyl; Kainic Acid; Male; Rats; Rats, Sprague-Dawley; Seizures; Status Epilepticus

High doses of pilocarpine are known to produce prolonged seizure activity in rats. Previous studies show that pretreatment with LiCl will sensitize rats to the convulsant effects of pilocarpine. Here we report that the anti-epileptogenic and anticonvulsant drug MK-801 (dizocilpine) paradoxically also sensitizes rats to pilocarpine induced limbic seizures and limbic status epilipticus (LSE). If rats were pretreated with MK-801, normally subconvulsive doses of pilocarpine rapidly produced LSE. LSE could be prevented by co-administration of either atropine or diazepam with MK-801.

Topics: Animals; Atropine; Diazepam; Dizocilpine Maleate; Drug Synergism; Electroencephalography; Limbic System; Male; N-Methylaspartate; Pilocarpine; Rats; Rats, Wistar; Seizures; Status Epilepticus

Anticholinergics, benzodiazepines and N-methyl-D-aspartate (NMDA) antagonists have been shown to modulate the expression of nerve agent-induced seizures. This study examined whether the anticonvulsant actions of these drugs varied depending on the duration of prior seizure activity. Rats implanted with electrodes to record electroencephalographic (EEG) activity were pretreated with the oxime HI-6 (125 mg/kg, IP) to prolong survival, and then challenged with a convulsant dose of the nerve agent soman (180 micrograms/kg, SC); treatment compounds (scopolamine, diazepam, MK-801, atropine, benactyzine, and trihexyphenidyl) were delivered IV at specific times after seizure onset. Both diazepam and MK-801 displayed a similar profile of activity: At both short or long times after seizure initiation the anticonvulsant efficacy of each drug remained the same. Diazepam, and especially MK-801, enhanced the lethal actions of soman by potentiating the respiratory depressant effects of the agent; scopolamine given prior to diazepam or MK-801 protected against the respiratory depression. Scopolamine and atropine showed a dose- and time-dependent effectiveness; the longer the seizure progressed the higher the dose of drug required to terminate the seizure, with eventual loss of anticonvulsant activity if the seizure had progressed for 40 min. In contrast, benactyzine and trihexyphenidyl showed a third profile of activity: There was a smaller increase in drug dosage required for anticonvulsant activity as seizure duration increased, and both drugs could terminate seizures that had progressed for 40 min. The early anticonvulsant action of anticholinergics is interpreted as a specific effect that blocks the primary cholinergic excitatory drive that initiates, and first maintains, nerve agent seizures. If allowed to progress, the seizure activity itself recruits excitatory neurotransmitter systems (i.e., NMDA) that eventually maintain the seizure independent of the initial cholinergic drive. This is indicated by the eventual ineffectiveness of scopolamine and atropine as the duration of the seizure progresses. Diazepam and MK-801 appear to act to moderate nerve agent seizures by enhancing inhibitory activity (diazepam) or dampening the secondarily activated noncholinergic excitatory system (MK-801). Benactyzine and trihexyphenidyl represent compounds that possibly have both anticholinergic and NMDA antagonistic properties.

Topics: Animals; Anticonvulsants; Atropine; Behavior, Animal; Benactyzine; Diazepam; Dizocilpine Maleate; Electrodes, Implanted; Electroencephalography; Male; Rats; Rats, Sprague-Dawley; Seizures; Soman; Trihexyphenidyl

Diazepam (10 mg/kg i.p.) or MK-801 (0.25 mg/kg i.p.) offered complete protection against corneal electroshock (30 mA x 0.2 s)-induced tonic seizures and lethality but failed to protect from aminophylline (150 mg/kg i.p.) + electroshock (15 mA x 0.2 s)-induced tonic seizures and lethality in mice. The diazepam (2.5 mg/kg i.p.) and MK-801 (0.25 mg/kg i.p.) combination completely protected the mice from aminophylline + electroshock-induced seizures and lethality. Sodium valproate (500 mg/kg i.p.) protected the mice from electroshock (30 mA) per se and aminophylline + electroshock (15 mA)-induced seizure and lethality. The present study established the neurosensitizing potential of a single, non-convulsive dose of aminophylline for electroconvulsion due to subthreshold intensity electroshock and demonstrated the prophylactic efficacy of sodium valproate and the synergistic therapeutic potential of diazepam and MK-801 combination against such seizure attacks.

Topics: Aminophylline; Animals; Diazepam; Dizocilpine Maleate; Electroshock; Male; Mice; Seizures; Valproic Acid

The convulsant profile of lindane was investigated in OF1 and NMRI mice lines in relation to other convulsants acting at the GABAA and NMDA receptor complexes. Thus, a specific GABA-gated chloride channel blocker, PTX, a GABAA receptor antagonist, PTZ, and an excitatory amino acid receptor agonist, NMDA, were used. Antagonism of the convulsant effects of each of these drugs was investigated with (+)MK-801, a blocker of the NMDA-operated cation channel, and with nifedipine, a voltage-dependent calcium channel antagonist. While no differences in potency for PTX or PTZ to induce seizures were observed between OF1 and NMRI mice, lindane was approximately 80 and 90% more potent in its ability to induce seizures and lethality, respectively, in OF1 than in NMRI mice. Brain lindane concentrations at the moment of convulsion, measured after ED100 doses of lindane (400 and 200 mg/kg for NMRI and OF1 mice, respectively), did not differ between OF1 and NMRI mice, suggesting that the different potency of lindane between these mouse lines is a consequence of pharmacokinetic factors. Furthermore, (+)MK-801 antagonized seizures induced by either lindane, PTX or PTZ with similar potencies in both mouse lines. These results, coupled with the different pharmacokinetics of lindane in OF1 and NMRI mice, suggest that the distinct effects of lindane in these mice are not mediated by different activities at either NMDA or GABAA receptor complexes. Nonetheless, nifedipine antagonized lindane-induced seizures with a three-fold higher potency in NMRI than in OF1 mice. In contrast, nifedipine failed to antagonize PTX and PTZ convulsions in both OF1 and NMRI mice. These results suggest that besides the GABAA receptor complex other mechanisms related to calcium mobilization may be involved in the convulsant action of lindane.

Topics: Animals; Anticonvulsants; Calcium Channel Blockers; Convulsants; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hexachlorocyclohexane; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Nifedipine; Pentylenetetrazole; Picrotoxin; Seizures; Sesterterpenes; Species Specificity

Topics: Animals; Anticonvulsants; Cocaine; Death; Dextrorphan; Dizocilpine Maleate; Glutamates; Kynurenic Acid; Male; Mice; Mice, Inbred ICR; Neurotoxins; Piperazines; Receptors, Neurotransmitter; Seizures

A study was performed to examine the specific binding of excitatory amino acid (EAA) receptor subtypes in 5 brain regions of rats kindled from the amygdala or hippocampus, using extensively washed and Triton X-100-treated membranes. Seven days after the last amygdala kindled seizure, [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10- imine maleate ([3H]MK-801) binding, which labels N-methyl-D-aspartate (NMDA)-sensitive receptor-linked cation channels, decreased significantly only in the amygdala of kindled rats compared to that of controls under equilibrium assay conditions. There was no significant change in [3H]MK-801 binding in the amygdala or hippocampus 7 days after the last hippocampal kindled seizure, or 28 days after the last amygdala kindled seizure. Nor was there a significant change in NMDA-sensitive [3H]glutamate, strychnine-insensitive [3H]glycine, [3H]spermidine, [3H]kainate or [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid ([3H]AMPA) binding in any brain region 7 days after the last amygdala kindled seizure, or in the hippocampus 28 days after the last amygdala kindled seizure. These results indicate that [3H]MK-801 binding sites labeling NMDA-sensitive receptor-linked cation channels in the amygdala undergo downregulation only transiently, but that none of the subcomponents of the NMDA receptor macromolecular complex exhibit enduring changes at steady state following the completion of amygdala kindling.

Topics: Amygdala; Animals; Brain Chemistry; Decerebrate State; Dizocilpine Maleate; Down-Regulation; Hippocampus; Kindling, Neurologic; Kinetics; Ligands; Male; Rats; Rats, Inbred Strains; Receptors, Amino Acid; Receptors, Cell Surface; Seizures

In mice, tonic convulsive seizure induced by intravenous administration of caffeine (adenosine A1, A2 receptors antagonist) was significantly potentiated by any one of L-PIA (adenosine A1 receptor agonist), NECA (adenosine A2 receptor agonist) and 2-ClAd (adenosine A1, A2 receptors agonist). The caffeine-induced seizure was unaffected by diazepam (benzodiazepine receptor agonist), but was inhibited by Ro 15-1788 (antagonist or partial agonist). beta-DMCM (antagonist or inverse agonist) increased the seizure. Muscimol (GABA-a receptor agonist), baclofen (GABA-b receptor agonist) and AOAA (GABA transaminase inhibitor) did not show significant effect on caffeine-induced convulsion. Bicuculline (GABA-a receptor antagonist) and picrotoxin (chloride channel blocker) significantly potentiated the convulsion at the doses which did not induce it. Caffeine-induced convulsion was potentiated by NMDA with its non-convulsive dose. CPP (competitive NMDA receptor antagonist) and MK-801 (non-competitive NMDA receptor antagonist) significantly inhibited the seizures. These results suggest that caffeine-induced seizure is not caused by blockade of adenosine receptors. Caffeine may act to beta-carboline sensitive benzodiazepine receptor (Type 1) which has no linkage with GABA-a receptor. Furthermore, it is implied that caffeine plays some role at NMDA receptor calcium ion channel complex.

Topics: Animals; Baclofen; Benzodiazepines; Caffeine; Diazepam; Dizocilpine Maleate; Flumazenil; Male; Mice; Muscimol; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Receptors, Purinergic; Seizures

Modulation of the NMDA receptor by the strychnine-insensitive glycine site was studied both in vitro and in vivo. In vitro the glycinergic stimulation of [3H]MK801 binding was measured in three different rat forebrain membrane preparations. An increased association rate of [3H]MK801 in the presence of glycine was observed. The binding of the radioligand was also enhanced by D-serine, whereas L-serine was less potent. The concentration-effect curves were shifted to the right by the glycine antagonist 7-chlorokynurenic acid (7CKA). In vivo modulation of the N-methyl-D-aspartate (NMDA) receptor was studied using NMDA induced convulsions in 7 day old rats. The NMDA effect was blocked by (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten,5,10-imine maleate (MK801) and D-(-)-2-amino-5-phosphono-pentanoic acid (AP5). The effect of a submaximal dose of NMDA was dose-dependently potentiated by 1-10 mg/kg D-serine, whereas higher doses of L-serine were needed to obtain a similar effect. 7CKA did not affect NMDA-induced convulsions but reduced the D-serine potentiation of NMDA responses. This study illustrates the ability of the strychnine-insensitive glycine site to modulate the NMDA receptor function both in vitro and in vivo.

Topics: 2-Amino-5-phosphonovalerate; Animals; Animals, Newborn; Dizocilpine Maleate; Glycine; Kynurenic Acid; Male; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Serine; Stereoisomerism; Strychnine

alpha-Dendrotoxin (Dtx), a snake polypeptide, increases neuronal excitability by blocking certain fast-activating, voltage-dependent K+ channels. Thus, the behavioural, electrocortical (ECoG) and neuropathological effects of Dtx, injected into rat brain areas, were studied. A unilateral injection of 35 pmol of Dtx into the CA1 hippocampal area or the dendate gyrus (DG; upper blade) immediately produced motor and ECoG seizures, followed at 24 h by multi-focal brain damage and significant neuronal loss. Whilst brain damage was seen bilaterally, significant neuronal loss occurred only in regions (CA1, CA3, CA4 and DG) ipsilateral to the site of injection. A lower dose (3.5 pmol) of toxin elicited motor and ECoG seizures but failed to produce brain damage. Seizures were observed 50 min after injecting Dtx (35 pmol) into the amygdala, though significant neuronal loss was not evident. 4-Aminopyridine (100 nmol), given into the CA1 area elicited a similar motor and ECoG pattern to that of Dtx except no brain damage could be seen at 24 h. Systemic pretreatment with antagonists of N-methyl-D-aspartate receptors (MK-801 or CGP 37849) did not protect against the effects typically evoked by injecting Dtx into the CA1 area.

Topics: 2-Amino-5-phosphonovalerate; Animals; Brain Diseases; Dizocilpine Maleate; Elapid Venoms; Electroencephalography; Hippocampus; Injections; Male; Nerve Degeneration; Neurotoxins; Potassium Channels; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

The effects of combined treatment with low doses (0.025-0.05 mg/kg i.p.) of the non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), and the antiepileptic drug, valproate, were studied in amygdala-kindled and non-kindled rats. MK-801, 0.05 mg/kg, did not exert anticonvulsant effects in fully kindled rats but increased the anticonvulsant potency of valproate, 100 mg/kg i.p. However, the increase in anticonvulsant activity was paralleled by a marked increase in adverse effects such as motor impairment and hyperactivity, resulting in a considerable reduction of the therapeutic index of the combined treatment compared to valproate alone. Furthermore, MK-801 potentiated the adverse effects but not the anticonvulsant activity of 50 mg/kg valproate. Combined treatment with MK-801 and valproate induced much less marked adverse effects in non-kindled rats than in kindled rats. The competitive NMDA receptor antagonist, CGP 37849 1 mg/kg i.p., did not alter the effects of valproate in kindled rats. The data on combined treatment with MK-801 and valproate substantiate the conclusion that kindling alters the susceptibility to manipulations of NMDA receptor-mediated events.

Topics: 2-Amino-5-phosphonovalerate; Animals; Dizocilpine Maleate; Drug Synergism; Female; Kindling, Neurologic; Motor Activity; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Valproic Acid

The excitatory and excitotoxic actions of the endogenous excitatory amino acid (EAA) neurotransmitter, glutamate, are mediated by activation of three common subtypes of EAA receptors: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/quisqualate and kainate receptors. EAA neurotransmitter systems play a number of physiological roles in the regulation and organization of neural systems during development. However, excessive activation of this neurotransmitter system is also implicated in the pathophysiology of several forms of acute and chronic brain injury. In this study, the susceptibility of the developing rat brain to AMPA/quisqualate receptor mediated injury was examined at eight postnatal ages (1-90 days). The receptor agonists, AMPA (25 nmol) or quisqualate (100 nmol), were stereotaxically microinjected unilaterally into the anterior striatum. The severity of resulting brain injury was assessed 5 days later by comparison of reductions in regional cortical and striatal cross-sectional areas. Microinjection of AMPA (25 nmol) produced widespread unilateral forebrain injury in the intermediate postnatal period (days 5-28). The severity of injury resulting from microinjection of a fixed dose of AMPA (25 nmol) transiently exceeded the severity of injury in adults between PND 5-28 with peak sensitivity occurring near PND 10. At PND 1, microinjection of AMPA produced a 24.5 +/- 1.7% reduction in striatal cross-sectional area, which is similar to the response observed in adult animals, and the lesion was confined to the injection site. Susceptibility to AMPA toxicity increased 2-fold from PND 1 to PND 5. At PND 10, the age of maximal sensitivity, the excitotoxic reaction to AMPA extended throughout the entire cerebral hemisphere and the mean striatal cross-sectional area was reduced by 81.7 +/- 3.9%. With advancing postnatal age, the severity of injury progressively diminished and the lesion became confined to the injection site. The developmental pattern of sensitivity to AMPA toxicity in other brain regions differed although peak sensitivity consistently occurred near PND 10. Microinjection of quisqualate produced a developmental pattern of striatal susceptibility similar to AMPA although quisqualate was a considerable less potent neurotoxin. In additional experiments, the in vivo pharmacology of AMPA and quisqualate mediated brain injury was evaluated in a PND 7 rat model in order to determine the neurotoxic cha

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Aging; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Analysis of Variance; Animals; Brain; Brain Injuries; Diazepam; Dizocilpine Maleate; Female; Ibotenic Acid; Male; N-Methylaspartate; Neurotoxins; Organ Specificity; Phenytoin; Quinoxalines; Quisqualic Acid; Rats; Rats, Inbred Strains; Seizures

Recent evidence indicates involvement of excitatory amino acid receptors sensitive to N-methyl-d-aspartate (NMDA) in the action of ethanol (EtOH). Pronounced inhibition of NMDA receptor function is seen in vitro with concentrations of EtOH corresponding to those present during alcohol intoxication in humans. The present study was devoted to investigate the role of NMDA receptors in the action of EtOH in rats. Acute experiments showed antagonism by EtOH of convulsions induced by intracerebroventricular injection of NMDA. A similar effect was seen with a high dose of diazepam. Convulsions induced by an agonist of another excitatory amino acid receptor subtype, kainate, were also inhibited by EtOH. An uncompetitive antagonist of NMDA receptors, 5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate (MK-801), potentiated EtOH-induced loss of righting, but attenuated the hypothermic action of EtOH. Moreover, MK-801 inhibited audiogenic convulsions in EtOH withdrawn rats. At the same time the effect of a proconvulsive dose of NMDA was not enhanced. Tolerance to the myorelaxant action of both EtOH and MK-801 upon repetitive administration was seen. Also some degree of cross-tolerance was observed. Moreover, MK-801 failed to modify EtOH preference in rats. The present results support involvement of NMDA receptors in expression of some acute and subchronic actions of EtOH and in expression of EtOH withdrawal.

Topics: Alcohol Drinking; Alcoholic Intoxication; Alcoholism; Animals; Binding, Competitive; Body Temperature Regulation; Brain; Dizocilpine Maleate; Ethanol; Male; Muscle Relaxation; Postural Balance; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Reflex; Seizures

Repeated exposure to cocaine results in sensitization to many of the behavioral effects of the drug. The present study was undertaken to examine the role of the N-methyl-D-aspartate (NMDA) type of glutamate receptors in the development of sensitization to the convulsive and lethal effects of cocaine in Swiss Webster mice. Repeated administration of subconvulsant doses of cocaine (45 mg/kg for 7 days) produced a progressive increase in the convulsive responsiveness to the drug. This phenomenon was accompanied by an increase in lethality rate after the 5th day of the treatment. Pretreatment with the noncompetitive NMDA receptor antagonist, MK-801 (5-methyl-10,11-dihydro-5H-dibenzo[a,d]- cyclohepten-5,10-imine) abolished completely the development of sensitization to cocaine-induced seizures and lethality. In addition, MK-801 attenuated cocaine-induced loss in animals body weight after 7 days of drug treatment. The lethal effects of acute administration of increasing doses of cocaine were also reduced by pretreatment with MK-801. In vitro receptor binding experiments demonstrated an increase (139% of control) in the number of NMDA receptors, labeled with the competitive NMDA receptor antagonist [3H]CGP 39653 ([3H]-2-amino-4-propyl-5-phosphono-3-pentenoic acid), in cortical membranes derived from the mice treated for 7 days with cocaine (45 mk/kg). In agreement with the latter finding, binding of [3H]MK-801 to the phencyclidine/NMDA site in cortical membranes of cocaine-treated mice was more sensitive to the stimulatory effect of glutamate compared to control (saline treatment).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Cerebral Cortex; Cocaine; Dizocilpine Maleate; Male; Mice; Receptors, N-Methyl-D-Aspartate; Seizures

Repeated administration of electroconvulsive stimuli (ECS) to mice once daily for a period of 7 days results in an enhanced locomotor response induced by apomorphine (1.0 mg/kg, IP). Pretreatment (30 min) with the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (0.01-1.0 mg/kg IP), suppressed ECS-induced seizure activity in a dose-dependent manner. MK-801 (0.01 and 0.033 mg/kg, IP) given 30 min before each ECS dose-dependently decreased apomorphine-mediated responses. Administration of MK-801 (0.033 mg/kg IP) 30 min after each convulsion had the same effect. These results indicate that MK-801 can abolish the ECS-induced enhancement of dopamine-mediated behaviour possibly by interfering with postictal processes. Thus, NMDA receptors seem to be involved in the behavioural changes and presumably also in the neural adaptations produced by repeated ECS.

Topics: Animals; Apomorphine; Behavior, Animal; Dizocilpine Maleate; Dopamine; Dose-Response Relationship, Drug; Electroshock; Male; Mice; Motor Activity; Receptors, N-Methyl-D-Aspartate; Seizures

Remacemide hydrochloride ((+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)- acetamide hydrochloride or FPL 1292AA) is a novel compound undergoing clinical trials for patients with generalized tonic/clonic and complex partial epilepsy. Remacemide exhibits efficacy against maximal electroconvulsive shock (MES) in rodents and seizures elicited by N-methyl-D,L-aspartate (NMDLA) in mice. Using rat synaptic membrane fractions, remacemide was shown to possess relatively weak noncompetitive binding to the ionic channel site of the NMDA (N-methyl-D-aspartic acid) receptor complex. With the hypothesis that activity against NMDLA-elicited seizures might be reflected by transformation to a more active metabolic species, the aim of the present study was to evaluate potential pharmacological effects of the 9 identified metabolites of remacemide which were all found in human and dog urine. Moreover, specific entities were recognized in plasma (including the rat's), as well as dog and rat cerebrospinal fluid. Five putative metabolites were also examined. A major route of metabolic transformation of remacemide in rats yields the formation of a pharmacologically active more potent desglycine derivative, namely FPL 12495 (+/-). Potency over the parent compound is revealed in the MES test in mice and rats, the NMDA-induced convulsions/mortality test in mice, and especially involving in vitro displacement of MK801 binding to the channel subsite of the NMDA receptor. The S isomer (FPL 12859) of this desglycinate is even more potent, while the R isomer is less potent than the corresponding racemate. Unlike the non-competitive NMDA antagonist, MK801, these desglycinates did not prevent kindled seizures. Three other identified metabolites show efficacy in the mouse and rat in vivo tests, namely the N-hydroxy-desglycinate (FPL 15053) and the p-hydroxy-desglycinates (FPL 14331 and FPL 14465). FPL 15053 exhibited modest activity in all tests. The only in vivo activity exhibited by the 2 p-hydroxy-desglycinates was evidenced in the MES test following i.p. and i.v. dosing. However, FPL 14331 was active in the MK801 binding assay. An oxoacetate metabolite, PFL 15455, failed to demonstrate any biological activity. Of potential metabolites tested 2 beta-hydroxy-desglycinates (FPL 14991 and FPL 14981) displayed modest activity in the MES test, however, only FPL 14981 prevented NMDLA-induced convulsions/mortality in mice and was 2-fold more active regarding MK801 binding. The hydroxy-methyl de

Topics: Acetamides; Animals; Anticonvulsants; Dizocilpine Maleate; Electroshock; Kindling, Neurologic; Male; Mice; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Seizures

It was found earlier that imipramine, amitriptyline and citalopram enhanced the locomotor hyperactivity induced by MK-801, a non-competitive NMDA receptor antagonist, in rats. Now, three other antidepressants: (+)-oxaprotiline, an inhibitor of the uptake of noradrenaline, (-)-oxaprotiline, an enantiomer devoid of any effect on the uptake of noradrenaline and fluoxetine, an inhibitor of the uptake of 5-hydroxytryptamine, have been examined in male Wistar rats. All those antidepressants, given in a single dose, increased the MK-801-induced locomotor hyperactivity. That increase was completely antagonized by haloperidol and partly by SCH 23390 and (+/-)-sulpiride; prazosin was inactive. Repeated administration of antidepressants produced a similar but more potent (than acute one) enhancement of the action of MK-801. Also, in that case haloperidol and SCH 23390 produced the strongest antagonistic effect; (+/-)-sulpiride and prazosin had a distinctly less potent action. Another effect of MK-801, anticonvulsant activity (electroshock-induced convulsions), was not increased by the antidepressants studied. These results indicate that antidepressants with a different pharmacological profile, increased the MK-801-induced locomotor hyperactivity, this effect being probably indirectly mediated, at least in part, by a dopamine mechanism.

Topics: Animals; Antidepressive Agents; Benzazepines; Citalopram; Dizocilpine Maleate; Fluoxetine; Imipramine; Isomerism; Male; Maprotiline; Motor Activity; Prazosin; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Sulpiride

The effects of dextrorphan (DX) and dextromethorphan (DM) were tested using the electroencephalogram (EEG) and behavioral effects induced by topical cortical application of penicillin in rabbits. For comparison, the influence of the NMDA antagonists, dizocilpine (MK 801) and 3-((+-(-)2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP), and of pentobarbitone was investigated. Intracortical injection of 500 IU of penicillin produced an EEG spiking followed by a repeated generalization of the electrical and behavioral symptoms. Within a few minutes, DX (5-15 mg/kg, IV) or pentobarbitone (5-10 mg/kg, IV) reduced dose dependently and significantly (p less than 0.01) the interictal and ictal EEG and behavioral effects elicited by cortical injection of 500 IU of penicillin. Higher doses of pentobarbitone (20 mg/kg, IV) but not of DX (20 mg/kg, IV) completely blocked the ictal behavioral and EEG effects elicited by cortical injection of 500 IU of penicillin. Within a few minutes, MK 801 (0.1-0.2 mg/kg, IV) or CPP (10-20 mg/kg, IV) reduced dose dependently and significantly (p less than 0.01) the ictal EEG and behavioral effects elicited by cortical injection of 500 IU of penicillin, while they did not affect the penicillin-induced interictal EEG changes. Higher doses of MK 801 (0.3 mg/kg, IV) completely blocked the ictal behavioral and EEG effects elicited by cortical injection of 500 IU of penicillin. Within a few minutes, DM (10-20 mg/kg, IV) blocked the behavioral effects, but failed to affect either the interictal or the ictal EEG effects induced by cortical injection of 500 IU of penicillin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Behavior, Animal; Cerebral Cortex; Dizocilpine Maleate; Electroencephalography; Injections; Male; Morphinans; N-Methylaspartate; Penicillins; Pentobarbital; Piperazines; Rabbits; Receptors, N-Methyl-D-Aspartate; Seizures

The effects of drugs on the convulsions induced by the combination of a new quinolone antimicrobial, enoxacin, and a nonsteroidal anti-inflammatory drug, fenbufen, were studied in mice. The combination of enoxacin at 30 or 100 mg/kg, p.o. and fenbufen at 100 mg/kg, p.o. induced convulsions; and the mice died as a result of the convulsions. Pretreatment with either phenobarbital, phenytoin, valproic acid intraperitoneally, or morphine intravenously did not influence the convulsions. A high dose of diazepam or clonazepam prolonged the survival time, but could not prevent the mice from dying. After the occurrence of convulsions induced by enoxacin with fenbufen, administration of the excitatory amino acid antagonist MK-801 at 1 mg/kg, i.v. extended the survival time, even though all the mice died as a result of the convulsions. Simultaneous intravenous injections of MK-801 and diazepam suppressed the convulsions. This suppression was stronger than that produced by MK-801 or diazepam, injected separately. However, no mouse survived at the end. From these results, participation of both GABA-ergic and excitatory amino acidergic systems in the convulsions induced by enoxacin and fenbufen was discussed.

Topics: Amino Acids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Diazepam; Dizocilpine Maleate; Drug Interactions; Drug Therapy, Combination; Enoxacin; gamma-Aminobutyric Acid; Male; Mice; Phenylbutyrates; Seizures

The anticonvulsant activity of ucb L059 ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide) was evaluated in a range of animal models. ucb L059 was active after oral and intraperitoneal administration in both rats and mice, with a unique profile of action incorporating features in common with several different types of antiepileptic drugs. The compound was active, with ED50 values generally within the range of 5.0-30.0 mg/kg, in inhibiting audiogenic seizures, electrically induced convulsions and convulsions induced chemically by pentylenetetrazole (PTZ), bicuculline, picrotoxin and N-methyl-D-aspartate (NMDA). ucb L059 retarded the development of PTZ-induced kindling in mice and reduced PTZ-induced EEG spike wave discharge in rats. The R enantiomer, ucb L060, had low intrinsic anticonvulsant activity, showing the stereospecificity of action of the molecule although the actual mechanism of action remains unknown. Neurotoxicity, evaluated with an Irwin-type observation test, the rotarod test and open-field exploration, was minimal, with only mild sedation being observed, even at doses 50-100 times higher than the anticonvulsant doses; at pharmacologically active doses, the animals appeared calm but slightly more active. ucb L059 thus presents as an orally active, safe, broad-spectrum anticonvulsant agent, with potential antiepileptogenic and anti-absence actions.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Convulsants; Dizocilpine Maleate; Female; Kindling, Neurologic; Levetiracetam; Male; Mice; Mice, Inbred DBA; Motor Activity; N-Methylaspartate; Piracetam; Rats; Rats, Sprague-Dawley; Seizures

A putative role for endogenous excitatory amino acid systems in the mediation of the cardiovascular and toxic responses to acute administration of cocaine, was examined in spontaneously hypertensive and normal Wistar-Kyoto rats. Conscious, restrained, male hypertensive and normal rats (12 weeks of age) received either the non-competitive excitatory amino acid receptor antagonist, MK-801 (0.01-10 mg/kg, i.v.) or vehicle, 30 min prior to initiation of infusion of cocaine hydrochloride (1.25 mg/kg min, i.v.). Administration of MK-801 produced increases in mean blood pressure and heart rate in both hypertensive and normal rats. Resting rectal temperature was reduced by MK-801 only at the largest dose tested (10 mg/kg). Infusion of cocaine caused convulsions and death at doses of 27.8 +/- 2.3 and 48.2 +/- 5.7 mg/kg, respectively in the normals, and 21.2 +/- 2.5 (P < 0.05) and 31.1 +/- 3.4 (P < 0.05) in the hypertensive rats. Pretreatment with MK-801 abolished the enhanced sensitivity of the hypertensive rats to the toxicity of cocaine. The doses of cocaine required to cause death were significantly increased, in the hypertensive rats at doses > or = 0.05 mg/kg, an effect which was not evident, at any dose, in the normals. The maximally effective dose of MK-801 (0.5 mg/kg) increased the dose of cocaine required to cause lethality by 272% (P < 0.05) in the hypertensive rats; the increase produced by MK-801 in the normals (163%) was not significant. Cocaine-induced convulsions were abolished in both hypertensive and control rats with doses of MK-801 > 0.1 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Body Temperature; Body Weight; Cocaine; Dizocilpine Maleate; Heart Rate; Infusions, Intravenous; Injections, Intravenous; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Seizures; Species Specificity

This study assessed the behavioral and electrographic effects of (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine maleate (MK-801) (0.1 and 0.5 mg/kg, IP), a noncompetitive antagonist of the NMDA receptors, in hippocampal (HIP)-kindled cats. MK-801 at a higher dose significantly reduced the afterdischarge duration, but not the behavioral seizure stage, of HIP-kindled seizures. This anticonvulsant effect occurred in association with the appearance of severe behavioral toxicity and paradoxical worsening of background electroencephalogram characterized by profound spike and wave discharges. The present data suggest the dissociative effect of MK-801 on seizure activity and limitations of its clinical utility as an antiepileptic agent.

Topics: Animals; Behavior, Animal; Cats; Dizocilpine Maleate; Electroencephalography; Female; Hippocampus; Kindling, Neurologic; Male; Receptors, N-Methyl-D-Aspartate; Seizures

The behavioural and neuropathological effects of both systemic and intrahippocampal injections of paraquat dichloride (1,1'-dimethyl 4,4'-bipyridinium dichloride) were studied in rats. Paraquat (0.1-1.0 mumol) injected into the dorsal hippocampus, produced limbic motor seizures within a few minutes of injection followed by neuronal damage in the CA1 and CA3 pyramidal cell layers, pyriform cortex, dentate granule cell layer and in the hilus fascia dentata at 24 hr (n = 9 rats). A smaller dose of paraquat (10 nmol) was ineffective. The effects of intrahippocampal injections of paraquat (1 mumol) were prevented by administering it together with atropine (50 nmol; n = 6 rats) or by giving it 60 min. after MK 801 (0.3 mg.kg-1 intraperitoneally). Systemic injections of paraquat (20-100 mg.kg-1) also produced forelimb clonus and rearing in 10 out of 15 animals. Neuronal cell death was found 24 hr later in 9 of these rats and was restricted to the pyriform cortex, the brain region with the highest concentrations of paraquat. Atropine (150 mg.kg-1 intraperitoneally given 60 min. previously) completely prevented the motor seizures but cell death still occurred in 2 of the 6 animals tested. In conclusion, both systemic and intrahippocampal injections of paraquat produced behavioural excitation accompanied 24 hr later by brain damage and antagonist studies suggested involvement of muscarinic and NMDA receptors in the neurotoxic mechanism.

Topics: Animals; Atropine; Brain; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Paraquat; Rats; Rats, Wistar; Seizures

Antagonists of the N-methyl-D-aspartate (NMDA) type of excitatory amino acid (EAA) receptors blocked cocaine-induced stereotypy, locomotor stimulation and convulsions. These effects in general appear to involve selectively NMDA type of receptors. The results suggest that NMDA-activated systems are an integral component in the reaction sequences involved in the expression of several behavioral effects of cocaine.

Topics: Animals; Caffeine; Cocaine; Dextromethorphan; Dizocilpine Maleate; Haloperidol; Male; Mice; Mice, Inbred Strains; Motor Activity; N-Methylaspartate; Pipecolic Acids; Quinoxalines; Rats; Rats, Inbred Strains; Seizures; Stereoisomerism; Stereotyped Behavior

Using the low-frequency kindling technique, we studied the effects of chronic MK-801 and chronic methamphetamine (MAP) administration on hippocampal kindling seizure development. In experiment 1, MK-801 (0.05, 0.1 mg/kg i.p.) was administered 2 h before each electrical stimulation until kindling developed into stage-3 seizure. In experiment 2, we started daily electrical stimulations two weeks after the last injection of chronic MAP administration (6 mg/kg/day, 14 days). The number of stimulating pulses required for the triggering of epileptic afterdischarge (pulse-number threshold, PNT) was used as an indicator of the seizure threshold. PNT, afterdischarge duration (ADD) and behavioral seizure stage (BSS) of each induced seizure in the initial stage of kindling; the kindling rates for stage 3 and stage 5 seizures; seizure parameters at the completion of kindling of the drug-treated groups were recorded and compared to the values of each saline-treated control group. Our result showed that MK-801 administration prior to each electrical stimulation selectively and significantly increased PNT in the initial stage of kindling without affecting other seizure parameters. Chronic pretreatment of MAP caused a selective and significant decrease of PNT of the first two stimulations in the kindling process. Taken together with the previous studies, these results suggest that long-term potentiation plays an important role in the development of the excitability of seizure focus but not of the induced seizure's propagation in the hippocampal kindling phenomenon. Clinically MK-801 seems to be a more efficacious drug in preventing the induction of seizures than in suppressing the acquired seizures.

Topics: Animals; Dizocilpine Maleate; Hippocampus; Kindling, Neurologic; Male; Methamphetamine; Neuronal Plasticity; Rats; Rats, Inbred Strains; Seizures; Time Factors

Functional antagonists at the N-methyl-D-aspartate (NMDA) receptor complex produce anti-depressant-like actions in preclinical models. Thus, an injection of a glycine partial agonist (1-aminocyclopropanecarboxylic acid; ACPC), a competitive NMDA antagonist (2-amino-7-phosphonoheptanoic acid; AP-7) or a use-dependent cation channel blocker (MK-801) reduced immobility in the forced swim test (FST) with efficacies comparable to imipramine (Trullas and Skolnick 1990). Seven daily injections of ACPC (200-400 mg/kg) abolished the effects of both this compound (200-1200 mg/kg) and AP-7 (200-300 mg/kg) in the FST. The loss in effectiveness of ACPC required 7 days of treatment to become fully manifest, and was reversed by discontinuing treatment. Other agents active in the FST (e.g. MK-801, imipramine, and nifedipine) were unaffected by this regimen. Moreover, ACPC and AP-7 remained active in the FST following repeated injections of MK-801, AP-7, or imipramine. Chronic treatment with ACPC did not affect its actions in the elevated plus-maze, but significantly attenuated the convulsant and lethal effects of NMDA (125 mg/kg). Tissue levels of ACPC indicate the modified behavioral responses produced by chronic treatment are not attributable to pharmacokinetic factors. These findings suggest repeated administration of ACPC may effect an "uncoupling" of NMDA and glycine receptors, resulting in an apparent desensitization of the behavioral actions of substances acting at these sites.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Amino Acids, Cyclic; Animals; Anticonvulsants; Antidepressive Agents; Behavior, Animal; Brain Chemistry; Dizocilpine Maleate; Learning; Male; Mice; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Seizures; Swimming

In rats made susceptible to audiogenic seizures by exposing them to an intense noise at a critical time during development, subsequent noise exposure elicited seizures and induced the proto-oncogene c-fos in auditory regions of the brain. Cells showing Fos-like immunoreactivity were especially dense in dorsal and external cortices of the inferior colliculus, and were nearly absent after pretreatment with the N-methyl-D-aspartate (NMDA) antagonist MK-801. Noise exposure alone (i.e. no seizure) produced a localized zone of c-fos induction within the inferior colliculus, but only when presented during the time period when susceptibility to audiogenic seizures can be most effectively induced.

Topics: Acoustic Stimulation; Aging; Animals; Brain; Disease Models, Animal; Dizocilpine Maleate; Epilepsy; Gene Expression; Genes, fos; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred Strains; Seizures

The ability of [(+-)-5-aminocarbonyl-10,11-dihydro-5H-di-benzo [a,d]cyclohepten-5,10-imine (ADCI) and its structural analogs dizocilipine (MK-801) and carbamazepine to block ethanol withdrawal seizures was tested in mice made physically dependent upon ethanol. Three injections of either ADCI (ranging from 1.0-10.0 mg/kg), dizocilpine (ranging from 0.1-1.0 mg/kg) or carbamazepine (ranging from 17-50 mg/kg) were administered during the first 7 hr of ethanol withdrawal. The severity of ethanol withdrawal seizures was rated during the first 11 hr of withdrawal and again at 24 hr after withdrawal of ethanol. ADCI and dizocilpine suppressed the severity and occurrence of the withdrawal seizures in a dose-dependent fashion, whereas carbamazepine was ineffective in blocking the withdrawal seizures. The relative potencies of dizocilpine, ADCI and carbamazepine in suppressing ethanol withdrawal seizures corresponded with the relative potencies of the compounds in displacing [3H]dizocilpine from mouse cortical membrane preparations. These findings are consistent with the suggestion that blockade of N-methyl-D-aspartate-mediated neurotransmission is an effective treatment for decreasing ethanol withdrawal seizures. ADCI also blocked the occurrence of withdrawal-associated whole body tremors, whereas dizocilpine and carbamazepine were ineffective in blocking the tremors. The doses of ADCI, dizocilpine and carbamazepine that resulted in motor incoordination on an accelerating rotarod task were determined in groups of naive mice. Dizocilpine in doses as low as 0.3 mg/kg produced a decreased ability to remain on the rotarod, whereas ADCI up to 30 mg/kg did not affect rotarod performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anticonvulsants; Carbamazepine; Dizocilpine Maleate; Ethanol; Male; Mice; Mice, Inbred C57BL; Motor Activity; N-Methylaspartate; Seizures; Substance Withdrawal Syndrome; Tremor

To determine if respiratory depression is an important mechanism of cocaine-induced death in conscious rats.. Male Sprague-Dawley rats weighing between 200 and 300 g and fitted with cortical electrodes were pretreated intraperitoneally with either saline (vehicle), MK-801, or valproic acid for 30 minutes before challenge with 70 mg/kg IP cocaine followed by spontaneous breathing or mechanical ventilation after acute tracheostomy. Behavior, seizures, death, EEGs, and ECGs were observed and measured.. In group 1, animals received saline followed by cocaine. The incidence rates of seizures and death were 92% and 83%, respectively. Group 2 received saline followed by cocaine and then were ventilated mechanically through an acute tracheostomy after respiratory arrest (late mechanical ventilation). This group experienced seizures in 100% and death in 67% of animals. Group 3 also received saline followed by cocaine but were ventilated mechanically immediately after the first seizures (early mechanical ventilation). They had experienced seizures in 100% and death in 30%, the latter being significantly (P less than .025) reduced compared with group 1. In group 4, an anticonvulsant (1 mg/kg MK-801) was given before cocaine challenge, resulting in seizures in 10% (P less than .002 compared with group 1) and death in 90%. Group 5 received MK-801 followed by cocaine and then were ventilated mechanically after respiratory arrest (late mechanical ventilation). They experienced seizures in 20% (P less than .002 compared with group 1), and no animals in this group died (P less than .002 compared with group 1 or 4). Group 6 received an anticonvulsant (400 mg/kg valproic acid), followed by cocaine. This resulted in seizures in 20% (P less than .002 compared with group 1) and death in 90%. Group 7 received valproic acid followed by cocaine and then were ventilated mechanically (late mechanical ventilation). They experienced seizures in 30% (P less than .002 compared with group 1), and all animals survived (P less than .002 compared with group 1 or 6).. Early mechanical ventilation reduces cocaine toxicity. Control of seizure activity with specific anticonvulsants allows delayed mechanical ventilation to protect against cocaine toxicity. This suggests that respiratory depression in conjunction with seizure activity plays a major role in the mechanisms of cocaine-induced death in this model.

Topics: Animals; Cocaine; Death; Dizocilpine Maleate; Drug Synergism; Electrocardiography; Electroencephalography; Male; Rats; Rats, Inbred Strains; Respiration, Artificial; Respiratory Insufficiency; Seizures; Sodium Chloride; Tracheostomy; Valproic Acid

The repeated administration of pentylenetetrazol (PTZ) at a subconvulsant dose (30 mg/kg i.p., three times a week for nine weeks) produced kindling in 90% of rats under treatment. Pretreatment with the N-methyl-D-aspartate receptor antagonist, MK-801 (1 mg/kg i.p., 40 min before PTZ), prevented the behavioral manifestation (i.e. motor seizures) as well as the development of kindling. In fact, convulsions were not observed in rats pretreated with MK-801 either during the chronic PTZ administration or when challenged with PTZ three and 10 days after completion of the chronic treatment. The results suggest an involvement of excitatory amino acid neurotransmission in PTZ kindling.

Topics: Amino Acids; Animals; Dizocilpine Maleate; Drug Administration Schedule; gamma-Aminobutyric Acid; Injections, Intraperitoneal; Kindling, Neurologic; Male; Pentylenetetrazole; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Seizures; Synaptic Transmission; Time Factors

Intracerebroventricular (ICV) administration of kappa-agonists (PD 117302, U-50488H and U-69593) induced convulsions in a dose-related manner in mice. The dose at which 50% of animals convulsed (CD50) was in nmol ranges for all opioids. Among the opioids used, PD 117302 was the most potent convulsant. ICV administration of either vehicle alone or U-53445E, a non-kappa-opioid (+) enantiomer of U-50488H did not induce convulsions. The convulsive response of kappa-agonists was differentially susceptible for antagonism by naloxone and/or MR 2266. Collectively, these findings support the view that convulsions induced by kappa-agonists in mice involve stereospecific opioid receptor mechanisms. Furthermore, the convulsant effect of kappa-agonists could not be modified by pretreatment with MK-801, ketamine, muscimol or baclofen. It is concluded that kappa-opioid but not NMDA or GABA receptor mechanisms are involved in convulsions induced by kappa-agonists. These results are the first experimental evidence implicating stereospecific kappa-receptor mechanisms in opioid-induced convulsions in mice.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Baclofen; Benzeneacetamides; Benzomorphans; Cerebral Ventricles; Convulsants; Dizocilpine Maleate; Injections, Intraventricular; Ketamine; Mice; Mice, Inbred Strains; Muscimol; Naloxone; Narcotic Antagonists; Narcotics; Pyrroles; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Seizures; Stereoisomerism; Thiophenes

A hypothesis is offered which suggests that excitatory amino acid (EAA) receptor antagonists have a potential role in the management of cardiac and cardiovascular pathophysiology resulting from increased central autonomic discharge. This suggestion is based on evidence that endogenous EAA release occurs following cerebral hypoxic insults, that cerebral hypoxia is associated with a high incidence of circulatory damage and that local intracerebral injection of EAA receptor agonists stimulates cardiovascular function and causes cardiac necrosis. Clinical events that can be linked to cerebral hypoxia, EAA release and production of cardiac pathology include intracerebral hemorrhage, cerebral trauma and stress. Cocaine intoxication may also involve central EAA release and experimental data are presented which demonstrate that pre-treatment with the EAA receptor antagonist, MK-801, can antagonize cocaine toxicity in the conscious rat. Antagonists at EAA receptors may be clinically useful in the management of disease states where heart-brain interactions contribute to morbidity and mortality.

Topics: Animals; Blood Pressure; Cardiovascular Diseases; Cocaine; Dizocilpine Maleate; Heart Rate; Humans; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

Digoxin (7.5 micrograms icv) induced 'pop-corn' type of convulsions and 100% mortality. The GABA-ergic agents produced varying degree of protection against digoxin-induced neurotoxicity. Diazepam (4 mg/kg) offered significant protection whereas pentobarbital (5 mg/kg) and baclofen (5 mg/kg) markedly reduced per cent mortality, but ethanol (2 g/kg), progabide (50 mg/kg) and muscimol (0.5 mg/kg) as well as GABA (50 mg/kg) could not offer significant protection in doses used. GABA-ergic agonists; GABA, baclofen, diazepam and pentobarbital when administered along with MK-801 (0.5 mg/kg) a non-competitive NMDA antagonist, a potentiation of anticonvulsant action of MK-801 was observed. MK-801 showed potent anticonvulsant profile in dose range (0.25-1 mg/kg) studied. A synergistic influence of Mg2+ and K+ ions on NMDA receptor antagonism was also observed. A role of GABA-ergic facilitation and NMDA antagonism as a potential anticonvulsant approach in digoxin-induced convulsions in rats has been suggested.

Topics: Animals; Baclofen; Diazepam; Digoxin; Dizocilpine Maleate; Female; gamma-Aminobutyric Acid; Injections, Intraventricular; Male; Muscimol; Pentobarbital; Rats; Rats, Inbred Strains; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Salts; Seizures

Topics: 2-Amino-5-phosphonovalerate; Animals; Diet; Dizocilpine Maleate; Ethanol; Hippocampus; Mice; Mice, Inbred C57BL; Receptors, N-Methyl-D-Aspartate; Seizures; Substance Withdrawal Syndrome

Exposure to high doses of organophosphorus nerve agents such as soman, even with carbamate pretreatment, produces a variety of toxic cholinergic signs, including secretions, convulsions and death. Evidence suggests that soman-induced convulsions may be associated with postexposure brain neuropathology. The purpose of this study was to investigate the pharmacologic mechanism of action of soman-induced convulsions and of anticonvulsant drugs. Various classes of compounds were evaluated for their efficacy in preventing soman-induced convulsions in rats pretreated with the oxime HI-6 to increase survival time, along with various doses of the test compounds (IM) either in the absence or presence of atropine sulfate (16 mg/kg, IM) 30 minutes prior to a soman challenge dose (180 micrograms/kg, SC; equivalent to 1.6 x LD50) that produced 100% convulsions. Without atropine sulfate, only tertiary anticholinergics (scopolamine, trihexyphenidyl, biperiden, benactyzine, benztropine, azaprophen and aprophen), caramiphen, carbetapentane and MK-801 were effective anticonvulsants. In the presence of atropine sulfate, the benzodiazepines (diazepam, midazolam, clonazepam, loprazolam and alprazolam), mecamylamine, flunarizine, diphenylhydantoin, clonidine, CGS 19755 and Organon 6370 studied were effective. We have examined the possibility that diazepam may exert some of its anticonvulsant effects through cholinergic mechanisms and found that a reduced release of ACh into synapses after diazepam and atropine treatment may account for diazepam's anticonvulsant activity against soman. We also found that at anticonvulsant doses biperiden and trihexyphenidyl each significantly reversed the effects of soman on striatal levels of DOPAC and HVA, the metabolites of dopamine, and have concluded that in addition to actions on muscarinic receptors, the anticonvulsant effects of these anticholinergics in soman poisoning may be partially related to their actions on the striatal dopaminergic system. These findings allow us to postulate that central muscarinic cholinergic mechanisms are primarily involved in eliciting the convulsions following exposure to soman and that subsequent recruitment of other excitatory neurotransmitter systems and loss of inhibitory control may be responsible for sustaining the convulsions and for producing the subsequent brain damage. Future studies to confirm these neuropharmacological mechanisms are proposed.

Topics: Acetylcholine; Animals; Anti-Anxiety Agents; Anticonvulsants; Antidotes; Atropine; Brain Chemistry; Choline; Diazepam; Disease Models, Animal; Dizocilpine Maleate; Gas Chromatography-Mass Spectrometry; Male; Oximes; Parasympatholytics; Poisoning; Pyridinium Compounds; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Seizures; Soman

The involvement of excitatory amino acid (EAA) receptors in mediation of the toxic effects of cocaine was studied in male ICR mice. Cocaine HCl (90 mg/kg, IP) induced seizures in 95% and death within 24 h in 68% (n = 135) of the animals. There was a significant correlation (r = .54) between the time to onset of convulsions and the time to death in mice which died within 30 min of injection (n = 84). Pretreatment with selected EAA receptor antagonists 15 min prior to cocaine differentially blocked cocaine toxicity. Selective N-methyl-D-aspartic acid (NMDA) receptor antagonists (MK-801, dextrorphan, CPP) decreased both the incidence of seizures and mortality. A nonselective EAA antagonist, kynurenic acid, decreased lethality in doses which did not reduce convulsions. A similar action was observed following pretreatment with the selective kainic acid/AMPA receptor antagonist, GDEE. Antagonists at EAA receptors can provide significant protection against cocaine-induced toxicity. Moreover, the data provide evidence for the involvement of both NMDA and non-NMDA receptor subtypes in aspects of cocaine toxicity.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Anticonvulsants; Cocaine; Death; Dextrorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Glutamates; Kynurenic Acid; Male; Mice; Mice, Inbred ICR; Piperazines; Quinoxalines; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Time Factors

The effect of single administrations of MK-801 (5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) or PCP (phencyclidine) on the induction of audiogenic seizure susceptibility by noise in immature rats was examined. Treatments with these non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists resulted in increases in noise exposure-dependent susceptibility. In neonatally drug-treated rats, seizures during adulthood were found to occur with significantly higher incidence and severity. Furthermore, drug treatments were found to lengthen what is normally a restricted developmental period within which susceptibility can be induced by noise exposure. The drugs, however, had no inherent ability to induce audiogenic seizure susceptibility if given alone. Moreover, in already-susceptible rats, MK-801 exhibited predictable anticonvulsant effects. These data suggest acute PCP or MK-801 exposures may transiently exacerbate risks inherent in certain forms of trauma. The mechanism underlying these effects is unknown although certain inferences are possible and may reveal much about epileptogenesis in this model.

Topics: Acoustic Stimulation; Aging; Animals; Disease Susceptibility; Dizocilpine Maleate; Female; Male; Noise; Phencyclidine; Rats; Rats, Inbred Strains; Seizures; Time Factors

MK-801 (a potent non-competitive antagonist of N-methyl-D-aspartic acid-mediated events) in subcutaneous doses of 0.1 and 0.2 mg/kg increased the threshold for electroconvulsions and in doses of 0.0031 and 0.0125 mg/kg enhanced the protective activity of valproate against maximal electroshock-induced convulsions in mice. Valproate-induced side-effects (evaluated by means of dark-avoidance acquisition and retention testing and the chimney test) at its ED50 against maximal electroshock (i.e. 268 mg/kg) were pronounced whereas they were absent in the case of a combined treatment with MK-801 (0.0125 mg/kg) and valproate (91 mg/kg). This treatment provided 50% protection against maximal electroshock-induced seizures. Moreover, MK-801 (0.0125 and 0.05 mg/kg) potentiated the anticonvulsant action of phenobarbital, reducing phenobarbital-induced motor impairment totally at 0.05 mg/kg, but did not influence the protection offered by carbamazepine and diphenylhydantoin at 0.05 mg/kg. The N-methyl-D-aspartic acid antagonist did not affect the total plasma levels of either valproate or phenobarbital (as measured by immunofluorescence), so a pharmacokinetic interaction, in terms of total plasma levels at least, is unlikely to be involved in the observed effects. The finding that the combined treatment of MK-801 with valproate or phenobarbital, apart from the distinct potentiation of their anticonvulsant activities, is devoid of side-effects should be carefully considered.

Topics: Animals; Anticonvulsants; Behavior, Animal; Dizocilpine Maleate; Drug Synergism; Electroshock; Learning; Male; Mice; Motor Activity; Phenobarbital; Seizures; Valproic Acid

Chemical kindling was induced in the rat by chronic treatment with pentylenetetrazol (PTZ, 30 mg/kg, IP, three times a week for eight weeks). PTZ kindling was associated with a reduction in central GABAergic function, as reflected by a significant decrease in the density of 35S-t-butylbicyclophosphorothionate (35S-TBPS) binding sites in the cerebral cortex. The pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (1 mg/kg, IP, 40 min before each PTZ injection) prevented the development of kindling as well as the reduction in 35S-TBPS binding. The results suggest that NMDA receptors may play a role in the alterations of GABAergic function observed in PTZ-kindled rats.

Topics: Animals; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Convulsants; Disease Susceptibility; Dizocilpine Maleate; Kindling, Neurologic; Male; Pentylenetetrazole; Rats; Rats, Inbred Strains; Seizures; Sulfur Radioisotopes

The effect of the non-competitive N-methyl-D-aspartate antagonist MK-801 on the early development of kindling-induced potentiation was examined in the rabbit hippocampal dentate gyrus. MK-801 (0.5 mg/kg) was administered 2 h before each daily kindling stimulation was applied to the perforant path. This treatment continued for the first 10 days of kindling. MK-801 depressed the growth of the afterdischarge duration and suppressed development of behavioral seizures. MK-801 did not block kindling-induced potentiation of either the perforant path-dentate granule cell population spike or excitatory postsynaptic potential. Random impulse train stimulation and non-linear systems analytic techniques were used to examine kindling-induced potentiation of presumed GABAergic recurrent inhibitory circuits. Both the magnitude and duration of kindling-induced response inhibition, to the second of each pair of impulses within the train, were reduced in rabbits pretreated with MK-801. These results suggest that MK-801 differentially affects kindling-induced potentiation of excitatory and inhibitory circuits within the rabbit hippocampal dentate gyrus.

Topics: Analysis of Variance; Animals; Dizocilpine Maleate; Electric Stimulation; Evoked Potentials; Hippocampus; Kindling, Neurologic; Male; N-Methylaspartate; Rabbits; Seizures

Previous work, using membrane receptor binding techniques, demonstrated an increase in hippocampal MK-801 binding sites in mice after chronic ethanol ingestion. The current studies, using quantitative autoradiography, demonstrate that chronic ethanol ingestion also produces increases in MK-801 binding in cerebral cortex, striatum and thalamus, as well as in hippocampus. The persistence of changes in MK-801 binding paralleled the time-course for ethanol withdrawal seizure susceptibility. These results support the hypothesis that an increase in the number of NMDA receptor/channel complexes in hippocampus, and possibly other brain regions, plays a role in the generation or expression of ethanol withdrawal seizures.

Topics: Animals; Autoradiography; Brain; Brain Chemistry; Dizocilpine Maleate; Ethanol; Male; Membranes; Mice; Mice, Inbred C57BL; Receptors, N-Methyl-D-Aspartate; Seizures; Substance Withdrawal Syndrome; Time Factors

MK-801 is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist with anticonvulsant and neuroprotective properties. The action of MK-801 (0.05-10 mg/kg IP) was assessed against pentylenetetrazol-induced seizures (PTZ; 100 mg/kg SC; 30 min after MK-801) in rats aged 7, 12, 18, 25, and 90 days (N = 263). We observed pronounced ataxia and hypermobility after MK-801 pretreatment during the whole ontogenesis, and the animals exhibited head-weaving and body-rolls. After the combination of MK-801 and PTZ "wet dog shakes" were detected in 18-, 25-, and 90-day-old rats (never seen in controls receiving PTZ only). MK-801 only insignificantly modified the latencies of minimal (clonic) seizures in 18-day-old and older rats where this seizure type is regularly elicited. In 12-day-old rats an increased incidence of minimal seizures was detected. MK-801 nearly completely blocked or strongly delayed major (generalized tonic-clonic) seizures and attenuated the seizure severity during ontogenesis in a dose-dependent manner. Present results suggest the important role of NMDA receptors in the genesis of generalized tonic-clonic seizures whilst the role of NMDA receptors in minimal seizures appears to be negligible during the whole ontogenetic development.

Topics: Aging; Amino Acids; Animals; Dizocilpine Maleate; Epilepsies, Myoclonic; Male; Pentylenetetrazole; Postural Balance; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Seizures

Electroencephalographic (EEG) activity in neocortex of rats following intracerebroventricular (icv) administration of NMDA (0.25-2 nmol/10 microliters) and its modification by noncompetitive NMDA-receptor antagonists, dizocilpine (MK-801) (0.025-0.1 mg/kg, ip) and ketamine (10-50 mg/kg, ip) was recorded at 0, 0.5, 4, 8 and 24 hr with chronically implanted electrodes. NMDA (0.25 and 1 nmol) showed longer lasting decrease in frequency in cortical neurons while 2 nmol produced convulsions and death. Administration of MK 801 (0.05 mg/kg) and ketamine (50 mg/kg) prior to NMDA offered protection in 40% of animals against NMDA-induced convulsions and blocked NMDA-induced long term influence. However, ketamine and MK 801 showed an increase in percent amplitude and also had long lasting effects per se. In conscious mice, NMDA (0.5-10 nmol/microliters icv) induced dose dependent convulsions. Both MK 801 and ketamine showed potent anticonvulsant effect. Ethanol (0.5-2 g/kg, ip) also offered significant protection against NMDA-induced convulsions. MK 801 (0.1 mg/kg) when administered concurrently with ethanol (0.5 g/kg) exhibited synergistic anticonvulsant effect. The EEG study in rats and effect of NMDA in conscious mice provide a direct evidence for the role of NMDA-receptor system in convulsions and in anticonvulsant action of ethanol.

Topics: Animals; Cerebral Cortex; Dizocilpine Maleate; Electroencephalography; Ethanol; Ketamine; Male; Mice; N-Methylaspartate; Rats; Receptors, N-Methyl-D-Aspartate; Seizures

The effects of the non-competitive N-methyl-D-aspartate (NMDA) antagonists, (+)-MK-801 hydrogen maleate (MK-801) and phencyclidine hydrochloride (PCP), were tested against hypoxia-induced tonic convulsions and hippocampal epileptiform discharges. Systemic administration of MK-801 and PCP suppressed the hypoxia-induced tonic convulsions in dietary Mg(2+)-deficient mice in a dose-dependent manner. The ED50 values (and their 95% confidence limits) of MK-801 and PCP were 0.19 (0.14-0.26) and 1.14 (0.32-4.11) mumol/kg, respectively. These values were lower than those of the conventional anticonvulsants tested. Induction of epileptiform discharges following hypoxia was also prevented by the presence of MK-801 and PCP at concentrations of 5-30 microM. The hypoxia-induced epileptiform discharges, however, were reduced, but not blocked completely, by the application of MK-801 and PCP. These results strongly suggest that activation of NMDA receptors in the hippocampus plays a pivotal role in the induction of hypoxia-induced tonic convulsions in dietary Mg(2+)-deficient mice.

Topics: Animals; Anticonvulsants; Dizocilpine Maleate; Hippocampus; Hypoxia; Magnesium Deficiency; Male; Membrane Potentials; Mice; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Seizures

(+-)-5-Aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d] [a,d]cyclohepten-5,10-imine (ADCI), a tricyclic compound structurally related to dizocilpine (MK-801) and carbamazepine, was a potent anticonvulsant in the mouse maximal electroshock seizure test when administered i.p. (ED50, 8.9 mg/kg) or p.o. (ED50, 23.5 mg/kg), but failed to cause motor impairment except at substantially higher doses (TD50 values, 49.2 mg/kg i.p. and 293 mg/kg p.o.). ADCI was also protective against chemically induced seizures in mice, including those produced by 4-aminopyridine (ED50, 7.1 mg/kg s.c.) and pentylenetetrazol (ED50, 37.4 mg/kg s.c.). In addition, ADCI antagonized the behavioral effects and lethality of s.c. administered N-methyl-D-aspartate (NMDA: ED50, 15.2 mg/kg), but was a weaker antagonist of kainate-induced clonic seizures (ED50, 33.0 mg/kg), indicating that the drug is a selective functional NMDA antagonist. In common with other NMDA antagonists, ADCI retarded the development of amygdaloid kindled seizures in rats, but failed to attenuate the afterdischarge duration in fully kindled animals. Whole cell voltage clamp recordings from cultured hippocampal neurons demonstrated that ADCI selectively blocks inward current responses to NMDA in a use-dependent fashion without affecting responses to kainate or quisqualate, indicating that ADCI is a selective open channel (uncompetitive) blocker of the NMDA receptor-ionophore complex. ADCI blocked NMDA-evoked inward current responses with a potency (IC50, 14 microM) similar to that with which it displaces [3H]-1-[1-(2-thienyl)-cyclohexyl]piperidine from binding to NMDA receptor channels in rat brain homogenates (IC50, 11.3 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Animals; Anticonvulsants; Carbamazepine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Kindling, Neurologic; Male; Mice; Motor Activity; N-Methylaspartate; Rats; Rats, Inbred Strains; Seizures; Structure-Activity Relationship

The selective kappa-opioid receptor agonist CI-977, stereoselectively antagonised clonic seizures induced by slow i.v. infusion of N-methyl-DL-aspartate in the mouse. It was found to be more efficacious and 10-fold more potent than the competitive N-methyl-D-aspartic acid receptor antagonist CPP (3-(+/-)-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid). The anticonvulsant action of CI-977 was antagonised by norbinaltorphimine indicating a specific interaction with the kappa-receptor. The effect of CI-977 but not that of CPP was also antagonised by the glycine/NMDA receptor agonist D-serine. These results provide evidence for a possible interaction between the kappa-receptor and the glycine/NMDA receptor.

Topics: Animals; Anticonvulsants; Benzofurans; Dizocilpine Maleate; In Vitro Techniques; Mice; Mice, Inbred Strains; Naltrexone; Piperazines; Pyrrolidines; Radioligand Assay; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Receptors, Opioid, kappa; Seizures; Stereoisomerism

The influence of anticonvulsant treatment upon (1) chronically increased seizure susceptibility, (2) on late increases in peptide levels and (3) on seizure-induced brain damage was investigated during various stages of acute kainic acid (10 mg/kg i.p.)-induced seizures. The seizures were interrupted at various stages of the syndrome (50 min to 24 h after injection of the toxin) by injecting thiopental (50 mg/kg i.p.) or the excitatory amino acid antagonist, MK-801 (10 mg/kg i.p.). The increase in neuropeptide Y and somatostatin levels in the frontal cortex could be prevented by early injection of either anticonvulsant (up to 180 min after kainic acid). No protection against the increase in peptide levels was observed when the anticonvulsants were applied later. Kainic acid-induced neuronal damage in the amygdala, with glutamate decarboxylase as a neurochemical marker, was entirely prevented by interrupting seizures up to 2 h after kainic acid. Partial protection (about 40-50%) was even found when the anticonvulsant treatment was applied after the acute syndrome, as late as 8 h after kainic acid injection. Chronically increased seizure susceptibility induced by kainic acid was not prevented, even by early injection (90 min after kainic acid) of the anticonvulsant drugs. The data indicate that (1) the late increase in seizure susceptibility may be initiated early after injection of kainic acid. (2) the late increase in peptide levels may be related to the frequency of acute seizures rather than to a change in seizure threshold or brain damage and (3) even late anticonvulsant therapy may antagonize seizure-induced brain damage in the amygdala.

Topics: Animals; Anticonvulsants; Brain; Brain Chemistry; Dibenzocycloheptenes; Dizocilpine Maleate; Glutamate Decarboxylase; Kainic Acid; Male; Neuropeptide Y; Neuropeptides; Pentylenetetrazole; Rats; Rats, Inbred Strains; Seizures; Somatostatin

Antagonists at excitatory amino acid receptors, especially the N-methyl-d-aspartate (NMDA) subtype, have been shown to possess anticonvulsant and anxiolytic properties (Clineschmidt et al., 1982; Croucher et al., 1982; Bennett and Amrick, 1986). 7189 and 8319, two closely related benzeneethanamines, are potential novel anxiolytic agents which bind with high affinity to the NMDA receptor at the non-competitive site and are relatively non-toxic (LD50's-160 mg/kg, ip). 7189 and 8319 showed anxiolytic effects in schedule controlled conflict assays as well as in the social interaction (SI) and elevated plus maze (EPM) procedures in rats. Following intraperitoneal administration of 7189 at 20 to 60 mg/kg, conflict responding was increased from 2- to 7-fold in the modified Cook and Davidson and Geller conflict paradigms. 8319, at 2.5 to 5 mg/kg, produced a two fold increase in conflict responding. In the non-schedule controlled procedures, 7189 at 20 mg/kg increased SI time by 23% while in the EPM at 10 to 20 mg/kg, open arm exploration time increased by 41 to 77%. Likewise, 8319 at 2.5 and 5 mg/kg increased open arm exploration and SI time by 50 and 37%, respectively. In summary, 7189 and 8319 were efficacious in four behavioral procedures predictive of potential anxiolytic agents. Although these compounds have not been submitted for clinical evaluation, they may represent a new class of beneficial compounds for the treatment of anxiety.

Topics: Aniline Compounds; Animals; Anti-Anxiety Agents; Anticonvulsants; Behavior, Animal; Binding, Competitive; Diazepam; Dizocilpine Maleate; Dose-Response Relationship, Drug; Learning; Male; Mice; N-Methylaspartate; Piperazines; Rats; Rats, Inbred Strains; Seizures; Thiophenes; Tritium; Yohimbine

Intracerebroventricular (ICV) injection of N-methyl-D-aspartate (NMDA) was shown to induce generalized seizures in mice. The competitive NMDA antagonists DL-2-amino-5-phosphonovaleroate (DL-AP7) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), the NMDA "channel blocker" antagonist (+)-5-methyl-10,11-dihydro 5H-dibenzo-[a,d] cycloheptan-5,10-imine maleate (MK-801) and the strychnine-insensitive glycine antagonists kynurenic acid (KYNA) and 7-chloro-kynurenic acid (7-Cl-KYNA), when co-administered (ICV) with NMDA, antagonized NMDA-induced generalized seizures. Administration (ICV) of DL-AP7, CPP and MK-801 resulted in impared learning performance in a passive avoidance task in mice, with ED50 close to the anticonvulsant dose. The glycine antagonists KYNA and 7-Cl-KYNA at high doses significantly failed to affect performance in the same model of learning. The results indicate that compounds acting at the strychnine-insensitive glycine site may have a larger "therapeutic window" as anticonvulsants than antagonists of the NMDA receptor and channel.

Topics: 2-Amino-5-phosphonovalerate; Animals; Dizocilpine Maleate; Injections, Intraventricular; Kynurenic Acid; Learning; Male; Mice; N-Methylaspartate; Piperazines; Receptors, Glycine; Receptors, Neurotransmitter; Seizures; Strychnine

Effects of MK-801, adenosinergic agents and carbamazepine were investigated against hypoxic stress-induced convulsions and death in mice. MK-801, a N-methyl D-aspartate antagonist, offered a significant protective effect against hypoxic convulsions. Adenosinergic agents such as adenosine, 2-chloroadenosine, N6-cyclohexyladenosine and dipyridamole produced theophylline-sensitive protective effect as they dose-dependently prolonged the latencies for onset of convulsions and death. Pretreatment with adenosinergic agents and MK-801 markedly enhanced the protective effect of the stable analogs of adenosine namely, 2-chloroadenosine and N6-cyclohexyladenosine. However, pretreatment with combination of MK-801 and adenosine or dipyridamole did not show enhanced protective effect. Carbamazepine also exhibited dose-dependent theophylline-sensitive protective effect. The pretreatment with combination of carbamazepine and MK-801 showed significantly enhanced protective effect. The observed enhanced protective effect of MK-801 and adenosinergic agents was reversed by pretreatment with theophylline. These results indicate the possible involvement of adenosinergic mechanisms in preventing hypoxic stress-induced convulsions and the role of NMDA receptors in hypoxia-induced convulsions and death as MK-801 not only showed effect per se but also potentiated the response due to adenosinergic agents.

Topics: 2-Chloroadenosine; Adenosine; Animals; Carbamazepine; Dipyridamole; Dizocilpine Maleate; Drug Interactions; Female; Male; Mice; Seizures; Stress, Physiological; Theophylline

Bilateral inferior olive lesions, produced by systemic administration of the neurotoxin 3-acetylpyridine (3AP) produce a proconvulsant state specific for strychnine-induced seizures and myoclonus. We have proposed that these phenomena are mediated through increased excitation of cerebellar Purkinje cells, through activation of glutamate receptors, in response to climbing fiber deafferentation. An increase in quisqualic acid (QA)-displaceable [3H]AMPA [(RS)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid] binding in cerebella from inferior olive-lesioned rats was observed, but no difference in [3H]AMPA binding displaced by glutamate, kainic acid (KA) or glutamate diethylester (GDEE) was seen. The excitatory amino acid antagonists GDEE and MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10 imine] were tested as anticonvulsants for strychnine-induced seizures in 3AP inferior olive-lesioned and control rats. Neither drug effected seizures in control rats, however, both GDEE and MK-801 produced a leftward shift in the strychnine-seizure dose-response curve in 3AP inferior olive-lesioned rats. GDEE also inhibited strychnine-induced myoclonus in the lesioned group, while MK-801 had no effect on myoclonus. The decreased threshold for strychnine-induced seizures and myoclonus in the 3AP-inferior olive-lesioned rats may be due to an increase in glutamate receptors as suggested by the [3H]AMPA binding data.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Dizocilpine Maleate; Epilepsies, Myoclonic; Glutamates; Ibotenic Acid; Male; Olivary Nucleus; Pyridines; Quisqualic Acid; Rats; Rats, Inbred Strains; Seizures; Strychnine; Tritium

Selective breeding has produced replicate lines of mice that are prone (WSP) or resistant (WSR) to ethanol withdrawal seizures. Ethanol-naive WSP mice inherently have a greater number of hippocampal binding sites for the NMDA receptor-gated ion channel blocker, MK-801, than ethanol-naive WSR mice. After chronic ethanol ingestion, hippocampal (but not cerebral cortical) MK-801 binding sites increase in both lines of mice. However, the number of MK-801 binding sites in the ethanol-treated WSR mice does not exceed the number of MK-801 binding sites in untreated WSP mice. At the time of ethanol withdrawal, the number of hippocampal MK-801 binding sites in each line of WSP mice is 50-70% higher than the number of such sites in WSR mice. Given the past evidence for a role of the NMDA receptor in seizures, the results implicate hippocampal NMDA receptor-gated channels in the generation of ethanol withdrawal seizures.

Topics: Animals; Brain; Cerebral Cortex; Dizocilpine Maleate; Drug Resistance; Ethanol; Glycine; Hippocampus; Kinetics; Male; Membranes; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Seizures; Species Specificity; Substance Withdrawal Syndrome

Topics: Amino Acids; Animals; Brain; Brain Chemistry; Cerebral Cortex; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hippocampus; Injections, Intraperitoneal; Mice; Mice, Neurologic Mutants; Receptors, N-Methyl-D-Aspartate; Seizures

The ability of MK-801, an N-methyl-D-aspartate (NMDA)-channel antagonist, to suppress alcohol withdrawal seizures generated audio-genically was studied in adult male rats using a cross-over experimental design. MK-801 treatment reduced overall seizure score and proportion of rats seizing. In comparison to other seizure models, alcohol withdrawal seizures seem to be particularly sensitive to MK-801, suggesting that mechanisms which result in seizure susceptibility after withdrawal of chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes.

Topics: Acoustic Stimulation; Animals; Dibenzocycloheptenes; Diet; Dizocilpine Maleate; Ethanol; Male; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Substance Withdrawal Syndrome

Experimental febrile seizures can be evoked in epileptic chicks by elevation of their body temperature. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists [(3-(+/- )2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), DL-2-amino-7-phosphosphonoheptanoic acid (APH), DL-2-amino-5-phosphonovaleric acid (APV), D-alpha-aminoadipic acid (AAA), and DL-alpha, epsilon-diaminopimelic acid (DAP)] and the noncompetitive NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5, 10-imine maleate (MK-801) produced dose-dependent increases in latency to the onset of seizures. Of the drugs tested, MK-801 had the highest potency followed in order by CPP = APH greater than APV much greater than AAA greater than DAP. There was a high correlation (r = 0.995) between the dose capable of doubling seizure latency and the affinity of the competitive NMDA antagonists for the NMDA receptor as determined by in vitro binding assays. These data suggest that NMDA receptor mediated mechanisms may be involved in the production of seizures in response to hyperthermia.

Topics: 2-Amino-5-phosphonovalerate; 2-Aminoadipic Acid; Amino Acids; Animals; Chickens; Diaminopimelic Acid; Dibenzocycloheptenes; Dizocilpine Maleate; Fever; Phenotype; Piperazines; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Synaptic Membranes

Previously we have shown that delivery of rapidly recurring hippocampal seizures (RRHS) to awake rats causes a rapid kindling and that RRHS in urethane-anesthetized rats leads to a progressive lengthening of afterdischarges and diminution of paired pulse inhibition. The present experiments examined the relationship between the changes in afterdischarge durations and inhibition. Pre-treatment before RRHS with the non-competitive NMDA receptor antagonists MK-801 and ketamine blocked afterdischarge lengthening. MK-801 also prevented RRHS-induced changes in paired pulse inhibition. For pharmacodynamic and pharmacokinetic reasons the ability of ketamine to counteract RRHS-induced changes of paired pulse inhibition was not examined. MK-801 also blocked the rightward shift of stimulus intensity vs. population spike curves which RRHS caused. We suggest that RRHS leads to an enduring diminution of GABAergic inhibition and that this accounts, at least in part, for the lengthening of afterdischarges seen with recurrent hippocampal seizures. In addition, NMDA receptor activation appears to play a role in this decrease of the potency of GABAergic inhibition. However, mechanisms which are not dependent on NMDA receptor activation also play a critical role in hippocampal epileptogenesis.

Topics: Animals; Dibenzocycloheptenes; Dizocilpine Maleate; gamma-Aminobutyric Acid; Hippocampus; Ketamine; Male; Neural Inhibition; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

Prior biochemical and electrophysiological studies have shown that low doses of ethanol inhibited calcium influx through the N-methyl-D-aspartate (NMDA) receptor/ionophore. The present data show that chronic ethanol treatment results in an increase in the number of NMDA receptor/ionophore complexes in the hippocampus, a brain area known to be associated with ethanol withdrawal seizure activity. Treatment during withdrawal with NMDA-exacerbated handling induced withdrawal seizures in the ethanol-dependent mice, while administration of the NMDA receptor-associated calcium channel antagonist MK-801 decreased the occurrence and severity of the withdrawal seizures in a dose-dependent manner. The results are consistent with the hypothesis that the up-regulation of the NMDA receptor systems following chronic ethanol treatment may mediate the seizures associated with ethanol withdrawal in dependent animals.

Topics: Alcoholism; Animals; Behavior, Animal; Dibenzocycloheptenes; Diet; Dizocilpine Maleate; Ethanol; Hippocampus; Male; Mice; Mice, Inbred C57BL; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Substance Withdrawal Syndrome

1. The involvement of the haloperidol-sensitive, sigma recognition site and the N-methyl-D-aspartic acid (NMDA) receptor in the mediation of the discriminative stimulus properties of (+)-N-allylnormetazocine [+)-NANM, (+)-SKF 10,047), has been investigated in the rat by use of a two-lever, operant drug discrimination paradigm. 2. Six compounds with nanamolar affinity for the sigma recognition site [+/-)-pentazocine, (+)-3-(hydroxyphenyl)-N-propylpiperidine [+)-3-PPP), ditolylguanidine (DTG), haloperidol, (-)-butaclamol and BMY 14802) were investigated for their ability to generalise or antagonise the (+)-NANM discriminative stimulus. Each drug was tested at doses found in an ex vivo radioligand binding assay to displace [3H]-DTG from the central sigma recognition site by more than 40%. 3. While (+/-)-pentazocine (in the presence of naloxone) generalised and (+)-3-PPP partially antagonised the (+)-NANM cue, the other putative sigma ligands were ineffective either as agonists or antagonists at doses clearly occupying the sigma site in vivo. 4. Dose-dependent generalisation to the (+)-NANM cue was seen with the selective non-competitive NMDA receptor antagonist, MK-801, a compound devoid of significant affinity for the sigma recognition site. 5. (+/-)-Pentazocine was found to antagonise seizures induced in the mouse by NMDLA, a model reflecting antagonism of central NMDA receptors, and a strong correlation was found between the rank order of potency of compounds to generalise to the (+)-NANM discriminative stimulus and their potencies as anticonvulsants. 6. In conclusion, no evidence was found to substantiate the contention that the discriminative stimulus properties of (+)-NANM are mediated by the haloperidol-sensitive sigma recognition site. On the other hand, the results are consistent with the interoceptive stimulus being mechanistically based in the NMDA receptor complex.

Topics: Animals; Aspartic Acid; Binding, Competitive; Dibenzocycloheptenes; Discrimination, Psychological; Dizocilpine Maleate; Guanidines; Haloperidol; Male; Mice; N-Methylaspartate; Phenazocine; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Seizures

Bilateral intrastriatal injections of quinolinic acid (QA) (180 nmoles) induced weight loss and neurologic and behavioral deficits including convulsions, decreased catalepsy response to haloperidol, increased nocturnal locomotor activity, and abnormal feeding behavior in adult male Sprague-Dawley rats. Pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, MK801 (4 mg/kg IP) 30 min prior to stereotaxic surgery prevented the appearance of all QA-induced behavioral abnormalities and prevented weight loss. Twelve weeks after surgery the QA-lesioned animals recovered to sham levels on feeding behavior and nocturnal locomotor activity, but showed persistent reductions in haloperidol-induced catalepsy. Histological examination of the QA-lesioned brains showed extensive lesions of the dorsolateral striatum and frontoparietal cortex. MK801 pretreatment protected against these lesions. These results confirm that MK801 treatment prevents the appearance of neuropathological damage after QA neurotoxicity, and further show that neuronal protection with MK801 is correlated with the absence of QA-induced behavioral deficits.

Topics: Brain; Dibenzocycloheptenes; Dizocilpine Maleate; Feeding Behavior; Motor Activity; Pyridines; Quinolinic Acid; Quinolinic Acids; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

The effects of excitatory amino acid antagonists on convulsions induced by intracerebroventricular (i.c.v.) or systemic (s.c.) administration of the gamma-aminobutyric acidA (GABAA) antagonist bicuculline (BIC) were tested in mice. 3-[+/-)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP), 2-amino-7-phosphonoheptanoate (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate (MK-801) were used as representatives of N-methyl-D-aspartate (NMDA) antagonists. gamma-D-Glutamylaminomethylsulphonate (gamma-D-GAMS) typified a preferential kainate (KA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) represented a preferential quisqualate (QA) antagonist, and kynurenic acid (KYNA) was used as a mixed NMDA/KA antagonist. Bicuculline methiodide (BMI) induced clonic convulsions following i.c.v. administration with a CD50 of 0.183 nmol (range 0.164-0.204). The excitatory amino acid antagonists blocked clonic seizures induced by BMI in the dose of 0.224 nmol (approximately CD97) when coinjected into the lateral ventricle. CPP (ED50 0.0075 nmol) was the most potent anticonvulsant and was followed by AP7 (0.182 nmol), MK-801 (0.22 nmol), gamma-D-GAMS (0.4 nmol), KYNA (1.7 nmol) and CNQX (5.17 nmol). Muscimol (MSC), the GABAA agonist, blocked BMI-induced seizures with an ED50 of 0.25 nmol. Systemic (s.c.) administration of BIC induced in mice generalized seizures with a CD50 of 2.2 mg/kg (range 1.9-2.5) for clonus and CD50 of 2.4 mg/kg (range 2.2-2.7) for tonus.2+ the pathogenesis of seizures triggered by bicuculline in mice.

Topics: Animals; Bicuculline; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Mice; Muscimol; Pipecolic Acids; Piperazines; Piperidines; Receptors, Amino Acid; Receptors, Cell Surface; Seizures

N-Methyl-D-aspartate (NMDA) receptor antagonists inhibit both the kindling process and the expression of seizures in previously kindled adult rats. Experimental seizures are more readily produced in infant than adult rats, possibly related to a developmental predominance of NMDA receptor-mediated effects. If so, reduction of seizure susceptibility by NMDA receptor antagonists should be more dramatic in infant rats than in adults. We studied the effect of ketamine and MK-801 on kindling epileptogenesis and seizure expression in 15-day-old rats. Ketamine (5, 10, and 20 mg/kg) and MK-801 (0.033 and 0.1 mg/kg) both significantly increased the latency to stage 3 or 4 seizures in dose-dependent fashion. These results were similar to those found in adults but occurred at slightly lower doses. Ketamine 20 mg/kg and MK-801 0.33 mg/kg totally eliminated clinical seizure activity and nearly abolished afterdischarge in previously kindled infant rats, effects exceeding those reported in adults using doses up to 6 times as great. These results support the hypotheses that NMDA receptor-mediated neurotransmission plays an important role in seizure production and the increased seizure susceptibility in immature brain and raise the possibility that NMDA receptor antagonists could be useful antiepilepsy agents in young children.

Topics: Animals; Dibenzocycloheptenes; Dizocilpine Maleate; Ketamine; Kindling, Neurologic; Rats; Reaction Time; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

The effect of diazepam, haloperidol, MK-801, and propranolol in antagonizing behavioral symptoms induced by lethal doses of cocaine, amphetamine, and methamphetamine were studied in a rat model. Animals were first pretreated IP with potential antagonists, diazepam (2, 5, and 10 mg/kg), haloperidol (5, 10, and 20 mg/kg), propranolol (5, 10, and 20 mg/kg), MK-801 (0.5, 1.0, and 2.5 mg/kg), and then were challenged IP with cocaine (70 mg/kg) (LD85), d-amphetamine (75 mg/kg) (LD100), and methamphetamine (100 mg/kg) (LD90). Diazepam, at all doses, provided significant protection against cocaine- (p less than or equal to 0.01) and methamphetamine- (p less than or equal to 0.05) induced seizures and produced a dose-dependent effect against amphetamine-induced seizures. MK-801, at all doses, reduced seizures in all groups (p less than or equal to 0.01). Propranolol altered the incidence of methamphetamine-induced seizures. Significant protection against cocaine-induced death was afforded by diazepam (p less than or equal to 0.01) and propranolol (p less than or equal to 0.05). Significant protection against amphetamine-induced death was provided by haloperidol (all doses, p less than or equal to 0.1), MK-801 (all doses, p less than or equal to 0.1), and propranolol (10 and 20 mg/kg, p less than or equal to 0.1). No agent reduced the incidence of methamphetamine- (50 or 100 mg/kg) induced death. The failure of d-amphetamine antagonists to protect against methamphetamine-induced toxicity and death suggest that different mechanisms of toxicity may exist between these drugs.

Topics: Amphetamine; Animals; Behavior, Animal; Cocaine; Diazepam; Dimethyl Sulfoxide; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electrodes, Implanted; Haloperidol; Lethal Dose 50; Male; Methamphetamine; N-Methylaspartate; Propranolol; Rats; Rats, Inbred Strains; Seizures

The anticonvulsant effect of ethanol against N-methyl-D-aspartic acid-(NMDA), kainic acid-, and picrotoxin-induced convulsions was studied in rats. Ethanol (2 g/kg, ip) offered protection against these agents, and it was most effective against picrotoxin and least effective against kainic acid. MK801, NMDA receptor antagonist, also provided protection against these agents. However, it was most effective against NMDA and least effective against kainic acid. Ineffective doses of MK801 (0.1 mg/kg, ip) and ethanol (0.5 g/kg, ip), when administered concurrently, had a facilitatory anticonvulsant effect, thereby providing protection against mortality following severe convulsions induced by NMDA or picrotoxin, but not against kainic acid. The protective effect of ethanol against NMDA- and kainic acid-induced neurotoxicity, in contrast to picrotoxin-induced toxicity, was not reversed by imidazodiazepine, Ro 15-4513, an ethanol antagonist. Furthermore, Ro 15-4513 did not produce any proconvulsant effect with NMDA or kainic acid. These findings suggested that the anticonvulsant actions of ethanol may be attributed to its ability to antagonize NMDA-mediated excitatory responses and facilitate the GABAergic transmission.

Topics: Animals; Anticonvulsants; Aspartic Acid; Dibenzocycloheptenes; Dizocilpine Maleate; Drug Synergism; Ethanol; Kainic Acid; Male; N-Methylaspartate; Picrotoxin; Rats; Rats, Inbred Strains; Seizures

The effects of acute and subchronic administration of the noncompetitive NMDA receptor antagonist MK-801 on the duration and severity of amygdaloid-kindled seizures in rats were determined to evaluate its anticonvulsant activity. Both the highest acute (1000 micrograms/kg) and subchronic regimens (2 x 300 micrograms/kg, 7 days) produced significant reductions in the seizure stage and afterdischarge duration. Although ataxia may have affected the seizure stage, MK-801 attenuated the primary afterdischarge suggesting anticonvulsant effects in the fully amygdaloid-kindled rat. Since tolerance develops to the behavioral effects of MK-801, other noncompetitive NMDA antagonists related to MK-801 seem to warrant evaluation as anticonvulsants.

Topics: Amygdala; Animals; Anticonvulsants; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Kindling, Neurologic; Male; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Reference Values; Seizures

MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclo-hepten-5,10-imine maleate], a noncompetitive antagonist of the N-methyl-D-aspartate-type of excitatory aminoacid receptors, was measured in plasma and brain tissues after i.p. administration to rats by using a novel high-performance liquid chromatography assay. The drug reached maximal concentrations in plasma and brain within 10 to 30 min of injection (2 mg/kg) with an elimination half-life of 1.9 and 2.05 hr, respectively. Mean ratio of brain area concentration-time curve to plasma area concentration time curve was 12.5, referring to total plasma concentrations. MK-801 distributed almost equally between plasma and red cells (mean blood-to-plasma ratio averaged 1.2 +/- 0.2 when calculated 30 and 180 min from drug administration). Plasma and brain concentrations of MK-801 rose almost linearly from 0.5 to 4 mg/kg 30 min after injection and the brain-to-plasma ratio (12.9 +/- 2.8) was constant in the dose range studied. The distribution of the drug in various brain regions 30 and 180 min after 2 mg/kg i.p. showed no preferential concentration or retention in any of the areas studied. The anticonvulsant effect of MK-801 was evaluated against limbic seizures (measured by EEG) induced by intrahippocampal injection of 120 nmol of quinolinic acid, an agonist of the N-methyl-D-aspartate-type receptors, in freely moving rats. At 0.25 and 0.5 mg/kg, MK-801 significantly lowered by 71 to 77% the number of seizures and by 80% the total time spent in seizures (P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anticonvulsants; Brain; Dibenzocycloheptenes; Dizocilpine Maleate; Electroencephalography; Male; Prazosin; Pyridines; Quinolinic Acid; Quinolinic Acids; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

The interaction between GABAergic (barbiturates, diazepam, ethanol) and other (phenytoin) anticonvulsants and the N-methyl-D-aspartate (NMDA) receptor antagonist MK 801 in protecting rats against maximal electroshock (MES)- and picrotoxin-induced (10 mg/kg) convulsions was studied. MK 801 (0.1 to 5 mg/kg) showed anticonvulsant responses against MES-induced convulsions in a dose dependent manner, higher doses showing severe muscle relaxation, motor incoordination, and anticonvulsant action. It also produced stereotypic head movement, circling behavior, and affected locomotion. When subanticonvulsant dose (1 mg/kg) of MK 801 was simultaneously administered with subprotective doses of GABAergic anticonvulsants, it significantly potentiated the effects of barbiturates, as compared to other agents. At 1 mg/kg, MK 801 did not offer protection against tonic convulsions though protected (100%) the animals from mortality due to picrotoxin-induced convulsions. It potentiated the effect of a subprotective dose (5 mg/kg) of pentobarbital, but not of diazepam, against tonic convulsions. However, no mortality was observed in either group. The antiglutamate action of barbiturates, particularly that of pentobarbital, may contribute to the observed potentiating response between pentobarbital and MK 801.

Topics: Animals; Anticonvulsants; Diazepam; Dibenzocycloheptenes; Dizocilpine Maleate; Electroshock; Ethanol; Male; Motor Activity; Pentobarbital; Phenobarbital; Phenytoin; Picrotoxin; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Stereotyped Behavior

The impairment of rotarod ability and the convulsive activity of phencyclidine (PCP) and MK-801 were compared in male CD-1 mice. The putative interaction between nifedipine and PCP and MK-801 on these behavioral measurements was also quantitated and compared. MK-801 produced a dose dependent inhibition of rotarod ability with an ED50 of 0.5 mg/kg. Nifedipine potentiated the impairment of rotarod ability by MK-801. Both PCP and MK-801 produced convulsive behavior in mice which was characterized by jumping and wild running fits; the CD50 for MK-801 was 1.3 mg/kg. Nifedipine dose dependently inhibited the convulsions associated with MK-801 and PCP. PCP but not MK-801 increased [3H]nitrendipine binding to dihydropyridine (DHP) binding sites on mouse brain membranes. MK-801 blocked the effects of PCP on [3H]nitrendipine binding. These findings suggest that MK-801 is a potent PCP-like drug which interacts with nifedipine and neuronal DHP binding sites. Nifedipine's reduction of the hyperactivity and convulsions elicited by MK-801 may be of importance in the eventual development of MK-801 as an antiischaemic and anticonvulsant drug.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Convulsants; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Mice; Motor Activity; Nifedipine; Phencyclidine; Receptors, Nicotinic; Seizures

Repeated administration of the beta-carboline FG 7142 results in sensitisation to its convulsant effects (chemical kindling); acutely FG 7142 is not convulsant, but following several treatments full seizures develop. It has been suggested that the increased sensitivity results from changes in benzodiazepine (BZ)/GABA receptor function. The present experiments studied the ability of BZ receptor ligands and anticonvulsant drugs with diverse mechanisms of action to block the expression and development of kindling to once daily injection of FG 7142 (40 mg/kg, i.p.) in mice. In fully kindled mice, the BZ receptor agonists clonazepam, ZK 93,423 and CL 218,872, and the antagonists flumazenil and ZK 93,426 prevented FG 7142 convulsions, as did 2 anticonvulsants, sodium valproate, possibly acting by influencing GABAergic transmission, and ethosuximide. A further two substances, MK 801 and 2-chloradenosine which act respectively via glutamatergic and purinergic mechanisms were also effective. When administered concomitantly with repeated FG 7142, all of these substances prevented or strongly reduced the development of kindling. Phenytoin and carbamazepine were ineffective in protecting against FG 7142 convulsions in kindled mice, and in preventing the development of kindling when administered repeatedly together with FG 7142. Since MK 801 and 2-chloradenosine prevented kindling, these results suggest that an interaction of FG 7142 with BZ receptors is not sufficient to induce kindling, which may instead result from secondary changes in sites distant from BZ/GABA receptors.

Topics: Animals; Anticonvulsants; Carbolines; Clonazepam; Dibenzocycloheptenes; Dizocilpine Maleate; Female; Kindling, Neurologic; Mice; Pyridazines; Receptors, GABA-A; Seizures

The high pressure neurological syndrome (HPNS) occurs when man or animals are exposed to hyperbaric pressure. Four non-competitive N-methyl-D-aspartate (NMDA) antagonists - MK-801, phencyclidine (PCP), SKF 10,047 and ketamine were tested in rats for effects on the HPNS. All drugs were injected i.p. prior to compression; ketamine was also infused i.v. Control rats received saline. Rats were exposed individually to increasing helium pressure (PO2 0.5 atmospheres absolute ATA). Three endpoints were used to assess HPNS: onset pressures for tremor, myoclonus and convulsions. Neither MK-801 (0.03 and 0.3 mg/kg) nor SKF 10,047 (50 mg/kg) had any effect on the onset pressures for tremor, myoclonus or convulsions, although the type of seizure was modified from the clonic/tonic seizure seen in controls to purely clonic. PCP (5 mg/kg) had no effect on the endpoints, but pressure enhanced the excitation and stereotypy seen at 1 ATA. Ketamine (100 mg/kg i.p.) did not affect tremor or myoclonus; ketamine infused i.v. at pressure only prevented tremor and myoclonus at 'anaesthetizing' concentrations. Our results show that these non-competitive NMDA antagonists had little effect on HPNS, in contrast to competitive NMDA antagonists, such as AP7, which are highly effective. Possible explanations for this lack of effect include (1) interactions with NMDA receptor channels are pressure dependent; (2) other actions of these antagonists override their effects on the NMDA receptor channel.

Topics: Animals; Binding, Competitive; Dibenzocycloheptenes; Dizocilpine Maleate; Hyperbaric Oxygenation; Ketamine; Male; Myoclonus; Phenazocine; Phencyclidine; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Tremor

The selective non-competitive NMDA receptor antagonist, MK-801, potently blocked convulsions induced in the mouse by N-methyl-DL-aspartic acid (NMDLA) with an i.v. ED50 dose of 0.2 mg/kg. Similar doses of MK-801 were also effective in blocking seizures induced by pentylenetetrazol (PTZ), electroshock and by sound in audiogenic seizure-prone animals. Other less selective non-competitive NMDA receptor antagonists including phencyclidine (PCP), thienylcyclohexylpiperidine (TCP), (+)-N-allylnormetazocine [+)-NANM, (+)-SKF 10,047) and ketamine also blocked NMDLA-induced seizures with a rank order of potency of MK-801 greater than PCP greater than TCP = (+)-NANM greater than ketamine. The competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked NMDLA-induced seizures with an ED50 of 4.5 mg/kg, 22- and 560-fold more potently than the competitive antagonists, 2-DL-amino-7-phosphonoheptanoic acid (2-APH) and 2-DL-amino-5-phosphonovaleric acid (2-APV), respectively. MK-801 was the most potent of the non-competitive antagonists to induce a motor syndrome including head weaving, body rolling, increased locomotion and ataxia, characteristic of the behavioural response to PCP in the mouse. The syndrome was also present following injection of the competitive NMDA receptor antagonists, although they were generally less potent (probably a reflection of poor brain penetration) and less efficacious than the non-competitive antagonists. For all compounds except CPP, the anticonvulsant ED50 dose was close to the minimum effective dose to induce motor stimulation: CPP was 5- to 10-fold more potent as an anticonvulsant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anticonvulsants; Aspartic Acid; Behavior, Animal; Binding, Competitive; Dibenzocycloheptenes; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ketamine; Male; Motor Activity; N-Methylaspartate; Phenazocine; Phencyclidine; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

The anticonvulsant activity of two competitive antagonists of the N-methyl-D-aspartate (NMDA) receptor, 2-amino-7-phosphonoheptanoic acid (APH) and 3-[2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP), and two non-competitive NMDA antagonists, phencyclidine (PCP) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), were compared in 4 models of induced seizures in mice. All 4 drugs protected against tonic extensor seizures induced by pentylenetetrazol (PTZ), by submaximal (15 mA) electroconvulsive shock (ECS) and by maximal (50 mA) ECS. Similar orders of potency (i.e., MK-801 greater than PCP greater than or equal to CPP greater than APH) were seen in each of the 3 seizure models. All 4 drugs failed to block clonic seizures induced by picrotoxin in the dose ranges that protected from tonic seizures. These data are consistent with other data demonstrating that competitive and non-competitive NMDA antagonists have similar pharmacologic effects. These results also support the suggestion that the anticonvulsant effects of competitive and non-competitive NMDA antagonists are mediated by the NMDA receptor-ionophore complex.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Anticonvulsants; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Mice; Pentylenetetrazole; Phencyclidine; Piperazines; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

In an electrographic model of seizures in the hippocampal slice, both of the N-methyl-D-aspartate (NMDA) antagonists 2-amino-5-phosphonovaleric acid and 5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801) prevented the progressive development of seizures but did not block previously induced seizures. Thus, a process dependent on the NMDA receptor-ionophore complex establishes a long-lasting, seizure-prone state; thereafter the seizures depend on non-NMDA receptor-ionophore mechanisms. This suggests that there is an important distinction between epileptogenesis and seizure expression and between antiepileptogenic and anticonvulsant pharmacological agents.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Aspartic Acid; Dibenzocycloheptenes; Disease Models, Animal; Dizocilpine Maleate; Electric Stimulation; Electrophysiology; Epilepsy; Evoked Potentials; Hippocampus; In Vitro Techniques; N-Methylaspartate; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Valine

The effects of the N-methyl-D-aspartate receptor antagonist MK-801 and the dihydropyridine calcium channel antagonist nimodipine were assessed for their anticonvulsant activity alone and in combination against clonic convulsions to pentylenetetrazole (PTZ) and strychnine (STR) in mice. Nimodipine (2-20 mg/kg) and MK-801 (0.1 and 0.5 mg/kg) did not affect the number of mice displaying clonic convulsions to PTZ. However, nimodipine in a dose-dependent manner increased (100%) the latency to clonic convulsions and lethality (mortality from tonic extension convulsions and respiratory failure) following PTZ. In contrast, MK-801 did not increase the latency to PTZ convulsions, but prevented the lethal effects of PTZ. When combined, MK-801 and nimodipine produced a significant reduction in the number of animals (40-60%) displaying PTZ convulsions and a greater increase in the latency to PTZ convulsions than did nimodipine alone. In contrast, MK-801 decreased the onset time, and increased the severity of STR convulsions. A combination of MK-801 and nimodipine which afforded significant protection against PTZ convulsions did not affect STR convulsions. These findings suggest that MK-801 and nimodipine, while possessing significant anticonvulsant activity on their own, produce a potent anticonvulsant synergism against PTZ but not STR.

Topics: Animals; Anticonvulsants; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Male; Mice; Nimodipine; Pentylenetetrazole; Reaction Time; Seizures; Strychnine

Ketamine and MK-801 act at phencyclidine receptors to block transmitter activity through the N-methyl-D-aspartate (NMDA) subtype of glutamate (GLU) receptor. These agents also block the potent excitotoxic actions of NMDA and are of interest for their potential ability to protect against neurodegenerative processes mediated by the excitotoxic action of endogenous Glu at NMDA receptors. Here we show that degeneration of thalamic neurons caused by persistent seizure activity in the corticothalamic tract (putative glutamergic transmitter pathway) is prevented by systemic administration of ketamine or MK-801, despite the failure of these agents to eliminate persistent electrographic seizure activity recorded from cortex and thalamus.

Topics: Animals; Anticonvulsants; Bicuculline; Cerebral Cortex; Dibenzocycloheptenes; Dizocilpine Maleate; Electroencephalography; Ketamine; Nerve Degeneration; Neurons; Rats; Rats, Inbred Strains; Seizures; Thalamus

"Reverse tolerance" was produced in rats and mice by repeated exposure to either cocaine or amphetamine. The locomotorstimulant effect was studied in mice; stereotypy and convulsions in rats. MK-801, the NMDA antagonist, blocked the development of "reverse tolerance" to all three effects. In contrast, haloperidol selectively blocked "reverse tolerance" to cocaine-induced stereotypy but not to convulsions. The data suggest that the glutamate system participates in the mechanism of "reverse tolerance" to the dopaminergic effects of cocaine and amphetamine, as well as to the convulsant effect of cocaine.

Topics: Amphetamine; Animals; Anticonvulsants; Cocaine; Dibenzocycloheptenes; Dizocilpine Maleate; Drug Interactions; Drug Tolerance; Haloperidol; Male; Mice; Motor Activity; Rats; Rats, Inbred Strains; Seizures; Stereotyped Behavior

Phencyclidine (PCP) inhibits dopamine (DA) uptake and acts as a noncompetitive N-methyl-D-aspartate antagonist by binding to PCP receptors. The PCP analog N-[1-(2-benzo(b)thiophenyl) cyclohexyl]piperidine (BTCP, GK13) is a potent DA uptake inhibitor, but has low affinity for PCP receptors. The behavioral effects of BTCP were compared with those of PCP, ketamine, MK-801 and cocaine. In mice, BTCP, like cocaine, produced locomotion, sniffing and gnawing; haloperidol blocked these effects. PCP, ketamine and MK-801 produced locomotion, sniffing, swaying and falling. PCP, ketamine and MK-801 produced generalization in rats discriminating either cocaine, PCP or MK-801 from saline. Like cocaine, BTCP produced generalization in cocaine-discriminating rats only; haloperidol partially antagonized this effect. In pigeons, PCP-like catalepsy was produced by ketamine and MK-801, but not by BTCP. N-methyl-D-aspartate-induced convulsions in mice were antagonized by PCP, ketamine and MK-801, but not by BTCP or cocaine. Thus, BTCP shared only cocaine-like behavioral effects with PCP, ketamine and MK-801. A DA antagonist reduced the effects of BTCP. Therefore, the cocaine-like behavioral effects of BTCP may be mediated primarily by DA uptake mechanisms. However, PCP receptors, but not DA uptake mechanisms, may mediate the cocaine-like behavioral effects of PCP, ketamine and MK-801, because their order of potency in producing these effects (MK-801 greater than PCP greater than ketamine) is consistent with their potency order at PCP receptors, but not at DA uptake sites.

Topics: Animals; Behavior, Animal; Cocaine; Columbidae; Dextroamphetamine; Dibenzocycloheptenes; Dizocilpine Maleate; Dopamine; Haloperidol; Ketamine; Methylphenidate; Mice; Phencyclidine; Rats; Seizures; Structure-Activity Relationship

An in vivo radioligand binding assay for the N-methyl-D-aspartate (NMDA) receptor channel complex in the mouse brain has been developed using the non-competitive NMDA receptor antagonist [3H]MK-801. In vivo binding of [3H]MK-801 was displaced by MK-801 (ED50 = 0.17 mg/kg i.p.), (-)-MK-801 (1.0 mg/kg), thienylcyclohexylpiperidine (1.8 mg/kg), etoxadrol (5.1 mg/kg) and (+)-SKF 10,047 (34.5 mg/kg). The potency of these drugs in this in vivo binding assay was highly correlated (r = 0.97) with their functional effects as antagonists of N-methyl-DL-aspartate-induced tonic convulsions.

Topics: Affinity Labels; Animals; Anticonvulsants; Aspartic Acid; Binding Sites; Binding, Competitive; Dibenzocycloheptenes; Dioxolanes; Dizocilpine Maleate; Ion Channels; Male; Mice; N-Methylaspartate; Phenazocine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

Various compounds that have been identified in the literature as binding to the [3H]phencyclidine receptor site and as producing behavioral effects similar to phencyclidine (phencyclidine-like) protected mice from maximal electric shock-induced tonic-extensor seizures. These anticonvulsant effects appear to be due to blockade of the N-methyl-D-aspartic acid receptor, as recently reported for phencyclidine-like compounds. Phencyclidine-like compounds produced their anticonvulsant effects at doses that were also neurologically impairing.

Topics: Animals; Anticonvulsants; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroshock; Male; Mice; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

The effects of several excitatory amino acid receptor antagonists on sensory-evoked electromyographic activity induced by catechol have been studied in urethane-anaesthetised rats. 2-Amino-5-phosphono-valearic acid (1.2 mumol/kg i.c.), cis-2,3-piperidine dicarboxylic acid (1.4 mumol/kg i.c.), gamma-D-glutamyl-glycine (2.0 mumol/kg i.c.), 2-amino-7-phosphono-heptanoic acid (230 mumol/kg i.v.) and MK-801 (5 mg/kg i.p.) all significantly decreased the frequency of occurrence of those components of the sensory evoked EMG dependent on supraspinal structures, but were without effect on the spinal component.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Catechols; Dibenzocycloheptenes; Dipeptides; Dizocilpine Maleate; Electromyography; Female; Pipecolic Acids; Rats; Receptors, Amino Acid; Receptors, Cell Surface; Seizures; Valine

Dextromethorphan, its metabolite dextrorphan, phencyclidine, ketamine, MK-801, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid and DL-2-amino-7-phosphonoheptanoic acid were evaluated for potency to antagonize N-methyl-D-aspartate-induced convulsions following intraperitoneal administration using male CF-1 mice. Whereas reference anticonvulsants (e.g., phenytoin) were ineffective in this model, dextromethorphan and all competitive and noncompetitive N-methyl-D-aspartate antagonists blocked seizures. The results are consistent with the interpretation that dextromethorphan elicits some of its pharmacological responses via an interaction with receptors for excitatory amino acids.

Topics: Animals; Anticonvulsants; Aspartic Acid; Dextromethorphan; Dibenzocycloheptenes; Dizocilpine Maleate; Levorphanol; Male; Mice; N-Methylaspartate; Psychomotor Performance; Seizures