cyclic-gmp and Seizures

Repeated electrical stimulation of the brain can produce many epileptogenic effects including those which characterize the kindling model. Kindling stimulation, by definition, changes the brain is such a way that formerly subconvulsive stimuli can elicit electrographic and convulsive seizure activity. In addition, the kindled animal becomes more susceptible to many, but not all, other types of seizures. These facts suggest that kindling produces brain changes which may selectively model some types of epileptiform excitability. In order to understand the basis for such changes numerous neurochemical studies have been attempted in the last few years. Although many changes have been demonstrated to be produced by kindling, few studies have been designed to specifically examine the long-lasting (permanent) neurochemical correlates of kindling stimulation. In this review, neurochemical data relevant to kindling are presented and discussed in terms of their possible significance to the seizure susceptibility changes produced by kindling.

Topics: Acetylcholine; Amino Acids; Animals; Brain; Cyclic AMP; Cyclic GMP; Dopamine; Evoked Potentials; gamma-Aminobutyric Acid; Glutamates; Glutamic Acid; Kindling, Neurologic; Models, Neurological; Neurotransmitter Agents; Norepinephrine; Receptors, Neurotransmitter; Seizures

Topics: Animals; Biogenic Amines; Catecholamines; Cyclic AMP; Cyclic GMP; Epilepsy; gamma-Aminobutyric Acid; Humans; Mice; Neurotransmitter Agents; Seizures

Topics: Amygdala; Animals; Biogenic Amines; Brain; Convulsants; Cyclic AMP; Cyclic GMP; Electric Stimulation; Enkephalins; gamma-Aminobutyric Acid; Kindling, Neurologic; Neurotransmitter Agents; Rats; Receptors, Cell Surface; Receptors, Cholinergic; Receptors, GABA-A; Seizures

Topics: 4-Aminobutyrate Transaminase; Action Potentials; Alcohol Oxidoreductases; Aldehyde Oxidoreductases; Animals; Aspartic Acid; Brain; Cyclic GMP; Dyskinesia, Drug-Induced; Electric Stimulation; Electrophysiology; Epilepsies, Partial; gamma-Aminobutyric Acid; Glycine; Humans; Nervous System Diseases; Neurons; Seizures; Serotonin; Succinate-Semialdehyde Dehydrogenase; Succinates; Valproic Acid

Topics: Animals; Brain Chemistry; Cyclic AMP; Cyclic GMP; Humans; Phenytoin; Potassium; Seizures; Tetrodotoxin

Topics: Aminobutyrates; Animals; Anti-Anxiety Agents; Benzodiazepines; Cerebellum; Cyclic GMP; gamma-Aminobutyric Acid; Glutamates; Harmaline; Isoniazid; Mice; Neurons; Purkinje Cells; Rats; Seizures; Tremor

Based on the hypothesis that mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) are caused by impaired vasodilation in an intracerebral artery, the authors evaluated the effects of administering l-arginine, a nitric oxide precursor. Patients were administered L-arginine intravenously at the acute phase or orally at the interictal phase. L-arginine infusions significantly improved all strokelike symptoms, suggesting that oral administration within 30 minutes of a stroke significantly decreased frequency and severity of strokelike episodes.

Topics: Administration, Oral; Adolescent; Adult; Amino Acids; Arginine; Cerebral Arteries; Child; Child, Preschool; Cholesterol; Cyclic GMP; Female; Headache; Humans; Male; MELAS Syndrome; Nitric Oxide; Paresis; Seizures; Stroke; Treatment Outcome; Vasodilation; Vision Disorders; Vomiting

Sildenafil is a phosphodiesterase 5 inhibitor used for the treatment of erectile dysfunction and pulmonary hypertension. Proconvulsant effect is a serious adverse event associated with sildenafil use. Here, we investigated the possible proconvulsant effects of sildenafil in pilocarpine (PILO)-induced seizures model, which mimics some aspects of temporal lobe epilepsy. We also evaluated sildenafil's effects on hippocampal markers related to PILO-induced seizure, for instance, acetylcholinesterase (AChE) activity, oxidative stress and nitric oxide (NO) markers, namely nitrite, inducible NO synthase (iNOS) and neuronal NOS (nNOS). The influences of muscarinic receptors blockade on sildenafil proconvulsant effects and brain nitrite levels were also evaluated. Male mice were submitted to single or repeated (7 days) sildenafil administration (2.5, 5, 10 and 20 mg/kg). Thirty minutes later, PILO was injected and mice were further evaluated for 1 h for seizure activity. Sildenafil induced a dose- and time-progressive proconvulsant effect in PILO-induced seizures. Sildenafil also potentiated the inhibitory effect of PILO in AChE activity and induced a further increase in nitrite levels and pro-oxidative markers, mainly in the hippocampus. Repeated sildenafil treatment also increased the hippocampal expression of iNOS and nNOS isoforms, while the blockade of muscarinic receptors attenuated both sildenafil-induced proconvulsant effect and brain nitrite changes. Our data firstly demonstrated the proconvulsant effect of sildenafil in PILO-model of seizures. This effect seems to be related to an increased cholinergic-nitrergic tone and pro-oxidative brain changes. Also, our findings advert to caution in using sildenafil for patients suffering from neurological conditions that reduces seizure threshold, such as epilepsy.

Topics: Acetylcholinesterase; Animals; Cyclic GMP; Hippocampus; Male; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphodiesterase 5 Inhibitors; Pilocarpine; Reactive Oxygen Species; Seizures; Sildenafil Citrate

Increased neuronal excitability causes seizures with debilitating symptoms. Effective and noninvasive treatments are limited for easing symptoms, partially due to the complexity of the disorder and lack of knowledge of specific molecular faults. An unexplored, novel target for seizure therapeutics is the cGMP/protein kinase G (PKG) pathway, which targets downstream K

Topics: Animals; Anticonvulsants; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Carbamates; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Electroshock; Phenylenediamines; Recovery of Function; Seizures; Signal Transduction

The present study was designed to investigate the involvement of the nitric oxide (NO)/cyclic guanylate monophosphate pathway in pilocarpine-induced seizures in mice. Male Swiss mice (26-32 g) were used as the in vivo model. The following pharmacological tools were utilized: the non-selective NO synthase (NOS) inhibitor L-NAME (10 mg/kg, i.p.), a preferential inducible NOS (iNOS) inhibitor aminoguanidine (25 mg/kg, i.p.), a highly specific iNOS inhibitor 1400W (2.5 mg/kg, i.p.), the NO donor L-arginine (150 mg/kg, i.p.), and the soluble guanylyl cyclase inhibitor ODQ (10 mg/kg, i.p.). The animals were divided into groups (n = 8) and pretreated for 30 min before receiving pilocarpine (400 mg/kg, i.p.), while the control group received only pilocarpine. They were observed for 60 min to measure initial seizure latency, latency till death, and mortality. An administration of L-NAME or ODQ delayed the onset of initial seizure, increased latency till death, and produced a 25% survival rate. Aminoguanidine increased the initial seizure and latency until death, and administration of 1400W did not have an effect. Incremental increases of NO by L-arginine were capable of decreasing the seizure and death latency. These results support the idea that the constitutive NOS, probably neuronal NOS, followed by soluble guanylyl cyclase activation is involved in the convulsive responses caused by pilocarpine administration.

Topics: Amidines; Animals; Arginine; Benzylamines; Cyclic GMP; Disease Models, Animal; Enzyme Inhibitors; Guanidines; Guanylate Cyclase; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxadiazoles; Pilocarpine; Receptors, Cytoplasmic and Nuclear; Seizures; Soluble Guanylyl Cyclase

This study was undertaken to evaluate the effect of nitric oxide (NO) synthase inhibitors on benzodiazepine withdrawal syndrome in mice and rats. Diazepam withdrawal in mice was read out as intensification of the seizures induced by a subthreshold dose of pentetrazole. In rats, the withdrawal syndrome resulting from chronic administration of diazepam, chlordiazepoxide, clonazepam and temazepam was characterized by audiogenic seizures, hypermotility and weight loss. Administration of the non-selective NO synthase inhibitors N(G)-nitro-L-arginine (L-NOARG) and N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) significantly attenuated the withdrawal syndrome (i.e., pentetrazole-induced seizures) in diazepam-dependent mice. L-NOARG significantly suppressed hypermotility in clonazepam-dependent rats and inhibited the decrease in body weight observed after 12 h of withdrawal in chlordiazepoxide- and clonazepam-dependent rats. Moreover, a clear propensity of L-NOARG to protect benzodiazepine-dependent rats against audiogenic seizures was observed. These findings suggest that the cGMP/NO system may participate in causing the signs of benzodiazepine withdrawal.

Topics: Animals; Benzodiazepines; Body Weight; Cyclic GMP; Enzyme Inhibitors; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar; Seizures; Substance Withdrawal Syndrome

Lithium is still the mainstay in the treatment of affective disorders as a mood stabilizer. Lithium also shows some anticonvulsant properties. While the underlying mechanisms of action of lithium are not yet exactly understood, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of lithium is mediated via NO-cGMP pathway. Injection of a single effective dose of lithium chloride (25 mg/kg) intraperitoneally (i.p.) increased significantly the seizure threshold (P<0.01). The anticonvulsant properties of the effective dose of lithium were prevented by pre-treatment with the per se non-effective doses of L-ARG [the substrate for nitric oxide synthase; NOS] (30 and 50 mg/kg) or sildenafil [a phosphodiesterase 5 inhibitor] (10 and 20 mg/kg). L-NAME [a non-specific NOS inhibitor] (5, 15 and 30 mg/kg), 7-NI [a specific neural NOS inhibitor] (30 and 60 mg/kg) or MB [a guanylyl cyclase inhibitor] (0.5 and 1 mg/kg) augmented the anticonvulsant effect of a sub-effective dose of lithium (10 mg/kg, i.p.). Whereas several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of lithium. Our findings demonstrated that nitric oxide-cyclic GMP pathway could be involved in the anticonvulsant properties of the lithium chloride. In addition, the role of constitutive NOS versus inducible NOS is prominent in this phenomenon.

Topics: Animals; Anticonvulsants; Arginine; Convulsants; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Indazoles; Injections, Intraperitoneal; Lithium Chloride; Male; Methylene Blue; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pentylenetetrazole; Phosphodiesterase Inhibitors; Piperazines; Purines; Seizures; Sildenafil Citrate; Sulfones; Treatment Outcome

Oxygen is a potent cerebral vasoconstrictor, but excessive exposure to hyperbaric oxygen (HBO(2)) can reverse this vasoconstriction by stimulating brain nitric oxide (NO) production, which increases cerebral blood flow (CBF)-a predictor of O(2) convulsions. We tested the hypothesis that phosphodiesterase (PDE)-5 blockers, specifically sildenafil and tadalafil, increase CBF in HBO(2) and accelerate seizure development. To estimate changes in cerebrovascular responses to hyperoxia, CBF was measured by hydrogen clearance in anesthetized rats, either control animals or those pretreated with one of these blockers, with the NO inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME), with the NO donor S-nitroso-N-acetylpenicillamine (SNAP), or with a blocker combined with l-NAME. Animals were exposed to 30% O(2) at 1 atm absolute (ATA) ("air") or to 100% O(2) at 4 or 6 ATA. EEG spikes indicated central nervous system CNS O(2) toxicity. The effects of PDE-5 blockade varied as a positive function of ambient Po(2). In air, CBF did not increase significantly, except after pretreatment with SNAP. However, at 6 ATA O(2), mean values for CBF increased and values for seizure latency decreased, both significantly; pretreatment with l-NAME abolished these effects. Conscious rats treated with sildenafil before HBO(2) were also more susceptible to CNS O(2) toxicity, as demonstrated by significantly shortened convulsive latency. Decreases in regional CBF reflect net vasoconstriction in the brain regions studied, since mean arterial pressures remained constant or increased throughout. Thus PDE-5 blockers oppose the protective vasoconstriction that is the initial response to hyperbaric hyperoxia, decreasing the safety of HBO(2) by hastening onset of CNS O(2) toxicity.

Topics: Anesthesia; Animals; Blood Gas Analysis; Blood Pressure; Cerebrovascular Circulation; Cyclic GMP; Guanylate Cyclase; Hyperbaric Oxygenation; Hyperoxia; Infusions, Intravenous; Male; Nitric Oxide Synthase Type I; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley; Seizures; Signal Transduction; Vasoconstriction

In order to assess the role of nitric oxide/cyclicGMP signaling pathway in the anticonvulsant effect of benzodiazepines, we studied the potential interaction of a phosphodiesterase type 5 inhibitor, sildenafil with the effect of diazepam on a mouse model of clonic seizures induced by intravenous infusion of GABA antagonist, pentylenetetrazole (PTZ). Administration of sildenafil (10 mg/kg; per se effective on seizure threshold) could abolish the anticonvulsive effect of diazepam, and a subeffective dose (5 mg/kg), when added to NO precursor L-arginine (50 mg/kg) could cause the same effect. Conversely, subeffective doses of diazepam (0.02 mg/kg) and NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 5 mg/kg), administered together, reversed the proconvulsive effect of sildenafil. Our findings indicate that the enhancement of NO/cGMP signaling pathway by sildenafil attenuates the anticonvulsant effect of the benzodiazepine prototype, diazepam. This suggests that the effects of facilitating GABA(A)-mediated inhibition and modulating NO pathways are additive and there might be a role for NO pathway in benzodiazepine effect against PTZ-induced seizures in mice.

Topics: Animals; Anticonvulsants; Cyclic GMP; Diazepam; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Male; Mice; Nitric Oxide; Pentylenetetrazole; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Seizures; Signal Transduction; Sildenafil Citrate; Substrate Specificity; Sulfones

Activity-dependent neuroprotective protein (ADNP) is widely distributed in the cytoplasm of neurons and astrocytes of the hippocampus. Kainic acid (KA)-induced seizures increases neuronal nitric oxide synthase (nNOS) in neurons and inducible NOS (iNOS) in glia cells which coincides with a reduction in ADNP in the hippocampus. Inhibitors of NOS or soluble guanylyl cyclase (sGC) activity reduce ADNP under basal conditions in the absence of seizures. Treating animals with these inhibitors prior to KA-induced seizure, in particular, L-NAME (N(G)-nitro-l-arginine methyl ester), advances the onset of the first seizure but reverses the loss of ADNP by 3 days after the first seizure. This suggests that the NO-cGMP pathway has a role in regulating ADNP under both basal physiological conditions and in the pathophysiological changes produced during epileptogenesis.

Topics: Animals; Cyclic GMP; Hippocampus; Homeodomain Proteins; Kainic Acid; Male; Nerve Tissue Proteins; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Seizures; Signal Transduction

Recent evidence indicates that sildenafil may exert some central effects through enhancement of nitric oxide (NO)-mediated effects. NO is known to have modulatory effects on seizure threshold, raising the possibility that sildenafil may alter seizure susceptibility through NO-mediated mechanisms. This study was performed to examine whether sildenafil influences the threshold of clonic and/or generalized tonic seizures through modulation of nitric oxide (NO)-cGMP pathway. The effect of sildenafil (1-40 mg kg(-1)) was investigated on clonic seizures induced by intravenous administration of GABA antagonists pentylenetetrazole (PTZ) and bicuculine and on generalized tonic seizures induced by intraperitoneal administration of high dose PTZ in male Swiss mice. The interaction of sildenafil-induced effects with NO-cGMP pathway was examined using nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), NOS substrate L-arginine, NO donor, sodium nitroprusside (SNP) and guanylyl cyclase inhibitor methylene blue (MB). Sildenafil induced a dose-dependent proconvulsant effect in both models of clonic, but not generalized tonic type of seizures. Pretreatment with either MB or L-NAME inhibited the proconvulsant effect of sildenafil, indicating the mediation of this effect by NO-cGMP pathway. In addition, a subeffective dose of sildenafil induced an additive proconvulsant effect when combined with either L-arginine or SNP. Sildenafil induces a proconvulsant effect on clonic seizure threshold that interacts with both exogenously and endogenously released NO and may be linked to activation of NO-cGMP pathway.

Topics: Animals; Arginine; Bicuculline; Cyclic GMP; Dose-Response Relationship, Drug; Male; Methylene Blue; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroprusside; Pentylenetetrazole; Phosphodiesterase Inhibitors; Piperazines; Purines; Seizures; Signal Transduction; Sildenafil Citrate; Sulfones

(E)-3-(2-Carboxy-2-phenylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acid, 1, is a potent and selective antagonist of the glycine site of the N-methyl-d-aspartate (NMDA) receptor. Using 3D comparative molecular field analysis (CoMFA) to guide the synthetic effort, a series of aryl diacid analogues of 1 were synthesized to optimize in vivo potency, duration of action, and binding activity. It was found that the incorporation of a substituted aromatic with an electron withdrawing group or a heterocyclic group at the 2-position of the 3-propenyl moiety of 1 gave compounds with better affinity and potency in the murine stroke model. Ultimately this led to the discovery of 3-[2-(3-aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid, 19, as a new potent selective glycine-site NMDA receptor antagonist.

Topics: Animals; Anticonvulsants; Binding Sites; Carboxylic Acids; Cyclic GMP; Glycine; In Vitro Techniques; Indoles; Male; Mice; Mice, Inbred DBA; Models, Molecular; Neuroprotective Agents; Phenylacetates; Quantitative Structure-Activity Relationship; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Stereoisomerism; Stroke

Hypericum perforatum L. is used in traditional medicine for its anticonvulsant property. We studied the anticonvulsant activity of the aqueous and ethanolic extracts of Hypericum perforatum aerial parts in mice in order to evaluate the traditional use of this plant. The pentylenetetrazole (PTZ) and the maximal electroshock seizure (MES) tests were used for assessing the anticonvulsive effects of this plant. In the PTZ test, the extracts (0.1-1g/kg, i.p.) delayed the onset of tonic convulsions and protected mice against mortality. In the MES test, both extracts did not showed an antiseizure activity. L-NAME (1-10 mg/kg, i.p.), a nitric oxide (NO) synthase inhibitor, reduced the anticonvulsant activity of the extracts. The results of this study indicate that the extracts of Hypericum perforatum aerial parts could contribute to the control of petit mal seizure and this effect may be partially mediated by nitric oxide pathway.

Topics: Animals; Anticonvulsants; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Electroshock; Ethanol; Hypericum; Injections, Intraperitoneal; Lethal Dose 50; Medicine, Traditional; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pentylenetetrazole; Plant Components, Aerial; Plant Extracts; Receptors, N-Methyl-D-Aspartate; Seizures; Water

Studies on the purinergic system normally deal with adenine-based purines, namely, adenine nucleotides and adenosine. However, a guanine-based purinergic system may also have important neuromodulatory roles. Guanine-based purines exert trophic effects on neural cells, protect brain slices in a model of hypoxia and stimulate glutamate uptake. In vivo, both guanosine 5'-monophosphate (GMP) and guanosine (GUO) protected against seizures. In this study, we investigated if the anticonvulsant effect of GMP is mediated by guanosine and if guanosine or GMP treatments were able to increase adenosine levels. Intraperitoneal (i.p.) treatments with 7.5 mg/kg GMP or guanosine prevented 50% of seizures by quinolinic acid (QA) and increased guanosine cerebrospinal fluid (CSF) levels around twofold and threefold, respectively; GMP and adenosine levels remained unchanged. Intracerebroventricular treatment with 960 nmol GMP prevented 80% of seizures and the 5'-nucleotidase inhibitor alpha-beta-methyleneadenosine 5'-diphosphate (AOPCP), when injected 3 min before, reduced this anticonvulsant effect to 30% protection as well as significantly decreased the conversion of GMP into guanosine measured in the CSF. This study shows that the previously reported effect of GMP as an anticonvulsant seems to be related to its ability to generate guanosine through the action of ecto-5'-nucleotidase.

Topics: Adenosine Diphosphate; Animals; Anticonvulsants; Cyclic GMP; Dose-Response Relationship, Drug; Guanosine; Male; Rats; Rats, Wistar; Seizures

Carbon monoxide (CO) and the excitatory amino acid glutamate both dilate cerebral arterioles in newborn pigs. The key enzyme in CO synthesis is heme oxygenase, which is highly expressed in neurons with glutamatergic receptor activity as well as cerebral microvessels. During seizures the extracellular level of glutamate is increased, which results in excessive depolarization of neurons. We hypothesized that CO is a mediator of excitatory amino acid-induced dilation of the cerebral microvasculature during seizures. Three groups of piglets were examined: 1) i.v. normal saline (sham control), 2) topical chromium mesoporphyrin (Cr-MP, 15 x 10(-6) M), and 3) i.v. tin-protoporphyrin (Sn-PP, 4 mg/kg). Synthetic metalloporphyrins (Cr-MP and Sn-PP) are heme oxygenase inhibitors, thereby reducing CO synthesis. Implanted closed cranial windows were used to monitor changes in pial arteriolar diameters. Seizures were induced by administration of i.v. bicuculline. Changes in pial arteriolar diameters were monitored during 30 min of status epilepticus. The percent increase in pial arteriolar dilation in the saline group during seizures was 68 +/- 3%. In the metalloporphyrin groups, the pial arteriolar dilation was markedly reduced (35 +/- 3% and 13 +/- 1%, for Cr-MP and Sn-PP, respectively; p < 0.05, compared with the saline group). We conclude that metalloporphyrins by inhibition of heme oxygenase and prevention of CO synthesis attenuate pial arteriolar dilation during seizures. Therefore, CO appears to be involved in cerebral vasodilation caused by glutamatergic seizures.

Topics: Animals; Animals, Newborn; Arterioles; Bicuculline; Carbon Monoxide; Cerebral Arteries; Cerebrovascular Circulation; Convulsants; Cyclic AMP; Cyclic GMP; Enzyme Inhibitors; GABA Antagonists; Glutamates; Heme; Heme Oxygenase (Decyclizing); Membrane Potentials; Mesoporphyrins; Metalloporphyrins; Nerve Tissue Proteins; Neurons; Pia Mater; Protoporphyrins; Seizures; Status Epilepticus; Swine; Vasodilation

Transient ischemia is known to lead to a long-lasting depression of cerebral metabolic rate and blood flow and to an attenuated metabolic and circulatory response to physiological stimuli. However, the corresponding responses to induced seizures are retained, demonstrating preserved metabolic and circulatory capacity. The objective of the present study was to explore how a preceding period of ischemia (15 min) alters the release of free fatty acids (FFAs) and diacylglycerides (DAGs), the formation of cyclic nucleotides, and the influx/efflux of Ca(2+), following intense neuronal stimulation. For that purpose, seizure activity was induced with bicuculline for 30 s or 5 min at 6 h after the ischemia. Extracellular Ca(2+) concentration (Ca(2+)(e)) was recorded, and the tissue was frozen in situ for measurements of levels of FFAs, DAGs, and cyclic nucleotides. Six hours after ischemia, the FFA concentrations were normalized, but there was a lowering of the content of 20:4 in the DAG fraction. Cyclic AMP levels returned to normal values, but cyclic GMP content was reduced. Seizures induced in postischemic animals showed similar changes in Ca(2+)(e), as well as in levels of FFAs, DAGs, and cyclic nucleotides, as did seizures induced in nonischemic control animals, with the exception of an attenuated rise in 20:4 content in the DAG fraction. We conclude that, at least in the neocortex, seizure-induced phospholipid hydrolysis and cyclic cAMP/cyclic GMP formation are not altered by a preceding period of ischemia, nor is there a change in the influx/efflux of Ca(2+) during seizure discharge or in associated spreading depression.

Topics: Animals; Bicuculline; Brain Ischemia; Calcium; Cyclic AMP; Cyclic GMP; Diglycerides; Electroencephalography; Fatty Acids, Nonesterified; Male; Phospholipids; Rats; Rats, Wistar; Seizures

A series of imidazo[1,5-a]quinoxaline piperazine ureas appended with a tert-butyl ester side chain at the 3-position was developed. Analogues within this series have high affinity for the gamma-aminobutyric acid A (GABAA)/benzodiazepine receptor complex with efficacies ranging from inverse agonists to full agonists. Many analogues were found to be partial agonists as indicated by [35S]TBPS and Cl- current ratios. Uniquely, a number of these analogues were found to have a bell-shaped dose-response profile in the alpha1 beta2 gamma2 subtype as determined by whole cell patch-clamp technique, where in vitro efficacy was found to decrease with increasing drug concentration. Many of the compounds from this series were effective in antagonizing metrazole-induced seizures, consistent with anticonvulsant and possibly anxiolytic activity. Additionally, several analogues were also effective in lowering cGMP levels (to control values) after applied stress, also consistent with anxiolytic-like properties. The most effective compounds in these screens were also active in animal models of anxiety such as the Vogel and Geller assays. The use of the piperazine substituent allowed for excellent drug levels and a long duration of action in the central nervous system for many of the quinoxalines, as determined by ex vivo assay. Pharmacokinetic analysis of several compounds indicated excellent oral bioavailability and a reasonable half-life in rats. From this series emerged two partial agonists (55, 91) which had good activity in anxiolytic models, acceptable pharmacokinetics, and minimal benzodiazepine-type side effects.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Anxiety; Biological Availability; Cell Line; Cerebellum; Convulsants; Cyclic GMP; Drug Evaluation, Preclinical; GABA Agonists; Imidazoles; In Vitro Techniques; Ligands; Male; Mice; Models, Molecular; Molecular Conformation; Pentylenetetrazole; Piperazines; Quinoxalines; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Receptors, GABA-A; Seizures; Structure-Activity Relationship; Urea

Central nervous system (CNS) oxygen (O2) toxicity is complex, and the etiology of its most severe manifestation, O2 convulsions, is yet to be determined. A role for nitric oxide (NO) has been proposed, although recent data have indicated that NO is synthesized from L-arginine by an enzyme, NO synthase (NOS). The enzyme is dependent on free calcium (Ca2+) concentration, therefore increases in intracellular Ca2+ may constitute the physiological and pathophysiological mechanisms for stimulating the synthesis of NO.. In this study, the intrasynaptosomal free calcium concentration ([Ca2+]i) was measured by the fluorescence of fura-2/AM, and cGMP (as an indirect marker of NO levels) was by radioimmunoassay (RIA) in the rat hippocampus after hyperbaric oxygen (HBO) exposure. We also investigated the effects of daurisoline (DSL, calcium channel blocker) and N-nitro-L-arginine (LNNA, NOS inhibitor) on the above biochemical parameters and the development of oxygen toxicity.. The results show that when the rats were exposed to HBO at 0.5 MPa the intrasynaptosomal Ca2+ and cGMP levels increased by two and three times, respectively, whereas with the use of DSL prior to HBO, the accumulation of [Ca2+]i and cGMP dropped to 56% and 60%, correspondingly. In the rats medicated with LNNA prior to HBO. [Ca2+]i and cGMP levels dropped to 70% and 36% of the HBO group. At the same time, the appearance of CNS oxygen toxicity was delayed and the survival rate increased. The protective effects of LNNA were reversed by L-arginine pretreatment. These findings suggest that the neuronal Ca2+ overload during HBO exposure is a major factor in the pathogenesis of CNS O2 toxicity, and cGMP-NO pathways may be directly involved in HBO-induced seizures.

Topics: Animals; Calcium; Central Nervous System; Cyclic GMP; Hippocampus; Hyperbaric Oxygenation; Male; Nitric Oxide; Nitric Oxide Synthase; Oxygen; Rats; Rats, Sprague-Dawley; Seizures; Synaptosomes

The effects of alaproclate and GEA-857 (2-(4-chlorophenyl)-1,1-dimethylethyl 2-amino-3-methylbutanoate) on the production of cyclic GMP in the rat cerebellum in vivo induced by stimulation of N-methyl-D-aspartate (NMDA) receptors were studied. Alaproclate per se at a dose of 20 mg/kg subcutaneously, did not influence the basal cGMP level. The increase in cGMP induced by harmaline (20 mg/kg subcutaneously) was dose-dependently antagonized by alaproclate (5-40 mg/kg subcutaneously). S-(-)-Alaproclate was 2-5 times more potent than the R-(+)-enantiomer. GEA-857 which in contrast to alaproclate is a very weak 5-HT uptake inhibitor shared the ability of alaproclate to inhibit the effect of harmaline on cGMP accumulation with similar potency to S-(-)-alaproclate. Alaproclate at 15 mg/kg subcutaneously blocked the increase in cGMP in cerebellum caused by NMDA itself at 200 mg/kg subcutaneously. In contrast to alaproclate, the K+ channel antagonist, 4-aminopyridine, 5 mg/kg subcutaneously, produced per se an increase in cGMP levels in the rat cerebellum by 300% which was antagonized by the NMDA receptor antagonists, dizocilpine, phencyclidine and (+/-)-CCP, the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester and by alaproclate. Alaproclate. Alaproclate and GEA-857 antagonized seizures induced by NMDA, 200 mg/kg subcutaneously at doses similar to those antagonizing the harmaline- and NMDA-induced elevation of cerebellar cGMP. Neither alaproclate nor GEA-857 caused any behavioural effects typical for uncompetitive NMDA receptor antagonists except a slight increase in motor activity and sniffing. The effect of alaproclate on the NMDA receptor-mediated increase in cGMP in rat cerebellum in vivo might be due to blockade of the cation channel of the NMDA receptor complex previously observed in in vitro experiments and these compounds seems to belong to the group of low-affinity uncompetitive NMDA receptor antagonists that might have clinical interest.

Topics: 4-Aminopyridine; Alanine; Animals; Behavior, Animal; Cerebellum; Convulsants; Cyclic GMP; Drug Interactions; Harmaline; Male; N-Methylaspartate; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Selective Serotonin Reuptake Inhibitors; Valine

PNU-101017 is a chemically novel ligand at the benzodiazepine recognition site of cloned GABAA receptors. It was reported to potentiate GABA-mediated chloride current in cultured cells with a moderate intrinsic activity and a biphasic dose-response relationship. In this study, we confirmed that PNU-101017 has a partial agonist-like effect in the antagonism of metrazole-induced seizures in mice. It produced no sedation or ataxia, but did antagonize diazepam-induced motor deficit of mice in the rotarod test. PNU-101017 was weakly active in anti-conflict anxiolytic tests, but attenuated the plasma corticosteroid response to mild stress in rats. It also antagonized stress-induced elevation of cerebellar cGMP levels in mice. Like chlordiazepoxide, it increased drinking of saline solution in thirsty rats. PNU-101017 did not potentiate the CNS-depressant effects of ethanol, and produced no evidence of physical dependence when administered repeatedly. Agonists with low intrinsic activity at the benzodiazepine receptor, such as PNU-101017, should be further explored for therapeutic uses.

Topics: Animals; Anti-Anxiety Agents; Avoidance Learning; Cells, Cultured; Cerebellum; Conflict, Psychological; Corticosterone; Cyclic GMP; Diazepam; Drinking Behavior; Electroshock; Ethanol; GABA-A Receptor Agonists; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Motor Activity; Muscle Relaxation; Pentylenetetrazole; Quinolines; Radioimmunoassay; Radioligand Assay; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Receptors, GABA-A; Seizures; Stress, Physiological

The present behavioral study was undertaken to investigate whether neuronal nitric oxide (NO) synthase mediates the abnormal consequences of increased NMDA receptor-mediated synaptic transmission in models of postural tremor, Parkinson's disease and epilepsy. We used 7-nitroindazole, a selective inhibitor of neuronal NO synthase, and NG-nitro-L-arginine (L-NAME), an unspecific NO synthase inhibitor, and compared their action with that of the competitive NMDA receptor antagonist 3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid (D-CPPene). In both mice and rats, 7-nitroindazole, L-NAME and D-CPPene dose dependently reversed the harmaline-induced increase of cerebellar cyclic guanosine-5'-monophosphate (cGMP) levels. For subsequent behavioral experiments we used doses of 7-nitroindazole, L-NAME and D-CPPene which were equipotent in preventing harmaline-induced cGMP increase. Harmaline-induced tremor in mice and rats was suppressed by D-CPPene, but not by 7-nitroindazole or by L-NAME. This effect of D-CPPene was not due to unspecific suppression of motor activity, since D-CPPene did not affect locomotor activity at doses which reduced tremor. D-CPPene, but not 7-nitroindazole and L-NAME potentiated the antiparkinsonian action of the dopamine agonist lisuride in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. D-CPPene antagonized seizures induced by intracerebroventricular injection of NMDA in mice. In contrast, 7-nitroindazole and L-NAME had only a tendency to prevent seizures and to delay the latency to onset of seizures. We conclude from these results that neuronal NO synthase does not serve as a major mediator of increased NMDA receptor-mediated synaptic transmission in animal models of Parkinson's disease, postural tremor and epilepsy. The novel observation that D-CPPene suppresses harmaline-induced tremor leads us to suggest that NMDA receptor antagonists should be considered as novel therapeutics for postural tremor.

Topics: Animals; Anticonvulsants; Behavior, Animal; Brain; Cyclic GMP; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Harmaline; Hydroxydopamines; Indazoles; Lisuride; Locomotion; Male; N-Methylaspartate; Nitric Oxide Synthase; Nitroarginine; Piperazines; Rats; Receptors, N-Methyl-D-Aspartate; Seizures

We planned to ascertain whether the administration of the anticholinesterase, tacrine (5 mg/kg i.p.), to rats pretreated 24 h before with lithium chloride (LiCl; 12 mEq/kg i.p.) produced any change in nitric oxide (NO) synthase activity in the hippocampus. A significant increase in hippocampal Ca(2+)-calmodulin-dependent NO synthase activity occurred 15 min after tacrine injection and was blocked by atropine (5 mg/kg i.p. given 15 min before tacrine) and by N omega-nitro-L-arginine methyl ester (300 micrograms given into one lateral cerebral ventricle 10 min before tacrine), a NO synthase inhibitor. A consistent cyclic guanosine 3',5'-monophosphate (cGMP) accumulation was also seen. In conclusion, the present results show that tacrine given to LiCl-pretreated rats produces a significant increase in NO synthase activity in the hippocampus and this may be responsible, at least in part, for seizures and related brain damage elicited by these drugs.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Atropine; Cerebral Cortex; Chlorides; Cyclic GMP; Hippocampus; Lithium; Lithium Chloride; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Wistar; Seizures; Tacrine

The mechanism of action of lithium, the primary treatment for bipolar affective disorder, is unknown but may involve inhibition of second messenger production in the brain. Therefore, the concentrations of three second messengers, inositol 1,4,5 trisphosphate (Ins 1,4,5P3), cyclic adenosine monophosphate (AMP), and cyclic guanosine monophosphate (GMP), were measured in rat cerebral cortex and hippocampus after acute or chronic lithium administration, as well as after treatment with the cholinergic agonist pilocarpine alone or in combination with lithium at a dose that induces seizures only in lithium pretreated rats. Neither acute nor chronic lithium treatment altered the hippocampal or cortical concentration of Ins 1,4,5P3, cyclic AMP, or cyclic GMP. Pilocarpine administered alone increased Ins 1,4,5P3 in both regions, did not alter cyclic AMP, and slightly increased cyclic GMP in the cortex. Coadministration of lithium plus pilocarpine caused large increases in the concentrations of all three second messengers and the production of each of them was uniquely attenuated: lithium reduced pilocarpine-induced increases of Ins 1,4,5P3 in the cortex at 60 min; chronic lithium administration reduced stimulated cyclic AMP production in the hippocampus; and chronic lithium treatment impaired stimulated cyclic GMP production in both regions. In summary, chronic lithium treatment appeared only to reduce Ins 1,4,5P3 and cyclic AMP concentrations after a long period of stimulation whereas cyclic GMP production was reduced by chronic lithium administration after both short and long periods of stimulation. Thus cyclic GMP was most sensitive to lithium and lithium attenuation of second messenger formation may be most important in excessively activated pathways.

Topics: Animals; Brain Mapping; Cerebral Cortex; Chlorides; Cyclic AMP; Cyclic GMP; Dose-Response Relationship, Drug; Hippocampus; Inositol 1,4,5-Trisphosphate; Lithium; Lithium Chloride; Male; Pilocarpine; Radioligand Assay; Rats; Rats, Inbred Strains; Seizures

Others have suggested that organophosphate-induced convulsions are related to changes in levels of cyclic nucleotides, especially in cerebella. We have examined this question by subcutaneously injecting male Sprague-Dawley rats (approx 250-300 gm) with three different doses of soman: a subconvulsive dose of 40 micrograms/kg, a convulsive dose of 120 micrograms/kg (which is approx 90% of the ED50 for convulsions) and a higher convulsive dose of 150 micrograms/kg. The incidence and severity of convulsions were monitored until the rats were sacrificed by focused microwave irradiation of the head at the following times after injections: 4 min, 10 min, 1 hr and 6 hr, which represent times prior to onset of convulsions, at onset of convulsions, at peak convulsive activity and during recovery from convulsions, respectively. Results showed that in rat striata, cerebella and thoracic spinal cord, neither changes in levels of cyclic AMP and cyclic GMP nor changes in ratios of cyclic AMP to cyclic GMP were correlated with soman-induced convulsions, i.e., none of the changes in cyclic AMP and cyclic GMP and/or in the ratios of cyclic AMP to cyclic GMP were related to the initiation of, maintenance of, or recovery from soman-induced convulsions.

Topics: Animals; Brain; Cyclic AMP; Cyclic GMP; Male; Rats; Rats, Inbred Strains; Seizures; Soman; Spinal Cord

The N-Methyl-D-aspartate (NMDA)-type receptor blocking properties of CGS 19755, a novel, rigid analog of 2-amino-5-phosphonopentanoate, were demonstrated in vitro by the ability of the compound to block NMDA-evoked [3H]acetylcholine release (pA2 = 5.93). CGS 19755 (0.045 and 0.224 mmol/kg i.p.) was shown to be active in vivo as well by its ability to block harmaline-induced increases in cerebellar cGMP. Finally, CGS 19755 blocked sound-induced seizures in DBA/2 mice completely at doses of 1.0 nmol i.c.v. or 0.1 mmol/kg i.p. Taken together, these data indicate that CGS 19755 is a potent and competitive NMDA antagonist in vitro which is also active in vivo.

Topics: Acetylcholine; Animals; Aspartic Acid; Binding, Competitive; Blood-Brain Barrier; Cerebellum; Cyclic GMP; Harmaline; Male; Mice; Mice, Inbred DBA; N-Methylaspartate; Pipecolic Acids; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

A number of different depressant and convulsant agents have been shown to alter accumulation of cerebellar cyclic GMP. Since the different hexachlorocyclohexane (HCH) isomers elicit different pharmacological responses in mammals, we examined their effects on the accumulation of cerebellar cyclic GMP. Mice received one of the HCH isomers and were sacrificed for determination of cyclic GMP concentrations one hour later. Gamma-HCH increased cyclic GMP while alpha and delta-HCH decreased it. In addition, alpha and delta-HCH prevented the increase in cyclic GMP due to the gamma isomer. Picrotoxin increased cyclic GMP in a manner similar to that of gamma-HCH while strychnine produced only a small increase. All three HCH isomers inhibited the binding of 3H-TBOB (a ligand for the GABA-A-receptor linked chloride channel) in mouse cerebellum. It is concluded that the different HCH isomers can have different effects on cerebellar cyclic GMP accumulation and that these effects may be mediated through actions at the GABA-A receptor linked chloride channel.

Topics: Animals; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Membrane; Cerebellum; Cyclic GMP; Hexachlorocyclohexane; Isomerism; Male; Mice; Picrotoxin; Seizures; Strychnine

Female Sprague-Dawley rats were maintained on a diet of barbital for 8 weeks, a period of time previously shown to result in tolerance to and dependence on the drug. After completing this course, the barbital was abruptly withdrawn and the selective antagonist of N-methyl-d-aspartate (NMDA), 2-amino-7-phosphonoheptanoic acid (APH), or saline was infused intracerebroventricularly over 48 hr. Control rats which had not received barbital, were similarly infused with either saline or APH. All animals were observed for 12-48 hr following the withdrawal of the barbital; spontaneous convulsions, previously reported to be numerous and severe after withdrawal of the drug, were counted and graded according to severity. Forty-eight hr after withdrawal of barbital, the rats were killed by focussed microwave irradiation and cerebellae were collected for later determination of levels of cGMP. Nine convulsions occurred in 29 rats withdrawn from barbital and infused intracerebroventricularly with APH, this contrasted markedly with 61 convulsions seen in 29 animals withdrawn from the drug and infused with saline. There was a 3-fold elevation of levels of cGMP in the saline-infused, barbital-withdrawn rats when compared to control rats infused with saline. This evaluation was markedly, although not completely, prevented by the intracerebroventricular infusion of APH. These data provide evidence that dicarboxylic amino acid pathways, specifically those acting through NMDA receptors, are involved in seizure activity seen following abrupt abstinence from barbital.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Aspartic Acid; Barbital; Barbiturates; Cerebellum; Cyclic GMP; Female; N-Methylaspartate; Rats; Rats, Inbred Strains; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Anticonvulsants; Cerebellum; Clonazepam; Cyclic AMP; Cyclic GMP; Diazepam; Male; Organophosphorus Compounds; Rats; Scopolamine; Seizures; Soman

3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) was synthesized as a rigid analog of 2-amino-7-phosphonoheptanoate, a previously known antagonist at the N-methyl-D-aspartate (NMDA) preferring, or NMDA-type, of excitatory amino acid receptor. CPP was found to be a potent, selective and competitive antagonist of NMDA-type receptors. CPP antagonized with an IC50 of 8 muM [3H]ACh release which was evoked from rat striatal brain slices by NMDA (50 muM). In contrast, the release of [3H]ACh evoked by elevated KCI was not inhibited by CPP even at a concentration of 100 muM. The antagonism by CPP of NMDA-evoked [3H]ACh release was competitive, with a pA2 of 5.66 for CPP, compared with a pA2 value of 5.22 for 2-amino-7-phosphonoheptanoate. CPP affected neither the uptake of L-[3H]glutamate nor the inhibition by aconitine of L-[3H]glutamate uptake, suggesting a lack of membrane-stabilizing or local anesthetic effects, and also suggesting that CPP itself may not be taken up through the L-glutamate membrane transporter. Moreover, [3H] CPP was not accumulated by synaptosomes (P2 fraction) which avidly accumulate L-[3H]glutamate, supporting the concept that this NMDA-type receptor antagonist acts at an NMDA-type receptor on the external surface of the plasma membrane. CPP (10 muM) failed to interact with any of 21 other putative neurotransmitter receptors including alpha-[3H]amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding (quisqualate-type receptor) and [3H]kainate binding (kainate-type receptor). Audiogenic convulsions in DBA/2 mice were blocked by CPP (ED50 = 1.5 mg/kg i.p.) as were NMDA-induced seizures in CF-1 mice (ED50 = 1.9 mg/kg i.p.). In both strains, CPP impaired the traction reflex at higher doses (ED50 = 6.8 mg/kg and 6.1 mg/kg and 6.1 mg/kg i.p. for DBA/2 and CF-1, respectively). The traction reflex impairment by CPP may be due to muscle relaxant effects of the compound, an explanation supported by the finding that CPP reduced muscle tone as assessed by electromyogram measurement in animals whose muscle tone had been increased by opiate administration. Finally, cerebellar cyclic GMP levels, known to be sensitive to neurotransmission via NMDA-type receptors, were decreased by CPP (ED50 = 4.7 mg/kg i.p.) in mice. In conclusion, based upon the competitive antagonism by CPP of NMDA-evoked [3H] ACh release in vitro and the antagonism of NMDA-induced convulsions in vivo, the data presented are consistent with competitive antagonism of NMDA-ty

Topics: Acetylcholine; Animals; Aspartic Acid; Cerebellum; Corpus Striatum; Cyclic GMP; Glutamates; Glutamic Acid; In Vitro Techniques; Kinetics; Male; Mice; Mice, Inbred DBA; N-Methylaspartate; Piperazines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

L-Cycloserine dose-dependently inhibited the activity of gamma-aminobutyric acid (GABA)-transaminase (GABA-T) and elevated the level of GABA in whole mouse brain with a peak effect 3-4 hr after a single intraperitoneal injection. At a dose (30 mg/kg) which elevated the level of GABA almost 4-fold, L-cycloserine moderately increased the content of alanine and slightly reduced that of aspartate, glutamate and glycine in the brain. L-Cycloserine (10-30 mg/kg, p.o. or i.p.) prevented tonic seizures induced by 3-mercaptopropionic acid (3-MPA) and audiogenic seizures in DBA/2 mice, without affecting those evoked by pentylenetetrazol, bicuculline and electroshock. Similarly small doses of L-cycloserine reduced the level of cGMP in the cerebellum of rats, prevented its elevation by 3-MPA and attenuated the hypothalamically-elicited rage reaction in cats. Larger doses of L-cycloserine (greater than 30-100 mg/kg) impaired the performance of mice in the rotarod, chimney and horizontal wire tests, and reduced spontaneous locomotor activity of rats. Upon repeated administration the inhibitory effect of L-cycloserine on the activity of GABA-T and on seizures elicited by 3-MPA in mice increased. In contrast, the depressant action of L-cycloserine on motor performance and locomotion declined in subchronically-treated mice and rats. The levels of amino acids in brain after repeated administration did not differ markedly from those in acutely-treated mice. It is suggested that small doses of L-cycloserine, probably by increasing GABAergic inhibition, reduce hyperexcitability in the brain in acute- and subchronically-treated animals. Larger doses of L-cycloserine, possibly by inducing multiple neurochemical changes, evoke central depressant effects which diminish during subchronic treatment.

Topics: 4-Aminobutyrate Transaminase; Amino Acids; Animals; Anticonvulsants; Brain Chemistry; Cats; Central Nervous System; Cerebellum; Cyclic GMP; Cycloserine; Female; Male; Mice; Motor Activity; Psychomotor Performance; Rage; Rats; Seizures

Seizures kindled with amygdaloid carbachol injections are transynaptic, dependent on activation of a specific population of muscarinic receptors, and some components of their expression could be mediated by intracellular second messengers. We measured cyclic GMP and cyclic AMP concentrations in micropunch biopsies of multiple brain regions after microwave fixation during the development and the expression of carbachol-kindled seizures in the rat. In the naive carbachol-injected amygdala, cyclic GMP concentrations rose from 1.03 +/- 0.15 pmol/mg protein to 2.21 +/- 0.46 after 2 min, and significant rises occurred in caudate, hypothalamus and contralateral amygdala. This response did not occur in implanted controls, after injection of mock cerebrospinal fluid, or when carbachol actions were blocked with atropine. The rise in cyclic GMP progressively disappeared upon repeated stimulation (injected amygdala on tenth stimulation: 0.72 +/- 0.23 pmol/mg protein). However, a late rise in both cyclic GMP and cyclic AMP concentrations occurred in many brain regions during convulsive seizures. These data suggest that during the development of kindling, changes in neuronal and synaptic excitability are associated with changes in intracellular second messengers.

Topics: Action Potentials; Amygdala; Animals; Brain; Carbachol; Cyclic AMP; Cyclic GMP; Habituation, Psychophysiologic; Kindling, Neurologic; Rats; Rats, Inbred Strains; Seizures

Dibutyryl cyclic GMP (DbcGMP) or dibutyryl cyclic AMP (DbcAMP) given to mice intracerebroventricularly in a dose of 200 or 400 nmol/head produced electroencephalographic and electromyographic changes corresponding to twitches, and clonic and tonic convulsions. Lower doses of DbcGMP or DbcAMP facilitated the pentylenetetrazol-induced clonic and tonic convulsions. Diazepam given intraperitoneally in a dose of 0.5 mg/kg suppressed clonic and tonic convulsions induced by DbcGMP and DbcAMP, but the twitches were not suppressed. These results suggest that these nucleotides lower the threshold for electrical discharges related to convulsion and facilitate the propagation of convulsion. Diazepam suppresses this facilitation.

Topics: Animals; Anticonvulsants; Brain; Bucladesine; Cyclic AMP; Cyclic GMP; Diazepam; Dibutyryl Cyclic GMP; Electroencephalography; Electromyography; Female; Mice; Mice, Inbred ICR; Nucleotides, Cyclic; Pentylenetetrazole; Seizures

The concentrations of cyclic 3', 5'-guanosine monophosphate (cGMP) and cyclic 3', 5'-adenosine monophosphate (cAMP) in the cerebellar and cerebral cortex were measured during lidocaine infusion and during bicuculline-induced seizures in rats. The rats were divided into three groups: control, lidocaine (0.74 mg/min) and bicuculline (1.2 mg/kg). The lidocaine group was divided into four stages according to the EEG pattern; desynchronized, synchronized, seizure and recovery. At the desynchronized and synchronized stages, cGMP and cAMP concentrations in both cerebellar and cerebral cortex remained unchanged except for a modest decrease in cerebral cGMP at the desynchronized stage. At the seizure stage, cerebellar cGMP increased from 5.2 +/- 0.9 to 9.2 +/- 1.4 pmol/mg protein and cerebellar cAMP decreased from 8.9 +/- 0.6 to 6.9 +/- 0.6 pmol/mg protein. These changes in concentrations at the seizure stage returned to the control at the recovery stage. During bicuculline-induced seizures, cGMP and cAMP concentrations increased strikingly in both cerebellar and cerebral cortex. These results indicated that lidocaine-induced seizures were accompanied by significant changes in cerebellar cyclic nucleotide concentrations in rats.

Topics: Animals; Bicuculline; Cerebellar Cortex; Cerebral Cortex; Cyclic AMP; Cyclic GMP; Electroencephalography; Lidocaine; Male; Rats; Rats, Inbred Strains; Seizures

The effect of substituting deuterium for hydrogen in the halothane molecule on anesthetic potency, motor activity, and cerebellar cyclic guanosine 3',5'-monophosphate (cGMP) content was studied in mice. The concentration of halothane required to abolish the righting reflex in 50% of the mice (ED50RR) was chosen as index of anesthetic potency; cerebellar control of motor activity was evaluated by the incidence of isoniazid-induced convulsions. The ED50RR for deuterated (D)-halothane was similar to that of halothane (0.87 +/- 0.04 and 0.88 +/- 0.03 vol%, respectively). Both D-halothane and halothane (0.15-0.90 vol%) protected the mice against isoniazid-induced convulsions and decreased cerebellar cGMP content in a dose-dependent manner. D-halothane and halothane were equipotent on both parameters. Thus deuteration did not alter the anesthetic potency, the anticonvulsant activity, or the effect on cerebellar cGMP content of the anesthetic. Furthermore, the reactivity of the C-H bond is probably not critical for these actions of halothane.

Topics: Animals; Cerebellum; Cyclic GMP; Deuterium; Drug Evaluation, Preclinical; Gas Chromatography-Mass Spectrometry; Halothane; Isoniazid; Male; Mice; Motor Activity; Seizures

The high seizure susceptibility in epileptic fowl is due to an autosomal recessive mutation. Cyclic AMP and cyclic GMP concentrations were determined in brains from two day old epileptic chicks (homozygotes) during an inter-ictal period as well as during and following a seizure evoked by stroboscopic stimulation. The data were compared to values obtained from non-epileptic carrier chicks (heterozygotes) sacrificed in an unstimulated state or subjected to the seizure evoking stimulus. During the inter-ictal state in epileptics no abnormalities were found in cyclic nucleotide concentrations indicating that the high seizure susceptibility is not related to abnormalities of these nucleotides. Although seizure activity in epileptics was associated with reduced cyclic AMP in the optic lobes this also occurred in carrier chicks subjected to the seizure evoking stimulus. The only significant changes in cyclic GMP levels, occurring as a result of seizures in epileptics, were an increase in cyclic GMP in the cerebral hemispheres during the seizure and a decrease in the optic lobes during the postictal period.

Topics: Animals; Brain; Chickens; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Epilepsy; Heterozygote; Homozygote; Seizures; Tissue Distribution

Topics: Animals; Brain; Cyclic AMP; Cyclic GMP; Epilepsy; Guinea Pigs; In Vitro Techniques; Nucleotides, Cyclic; Seizures

Topics: Acetylcholinesterase; Animals; Anticonvulsants; Central Nervous System; Cerebellum; Cholinesterase Inhibitors; Clonazepam; Cyclic GMP; Dibutyryl Cyclic GMP; Lethal Dose 50; Male; Organophosphorus Compounds; Rats; Rats, Inbred Strains; Seizures; Soman

Topics: Animals; Brain; Cerebral Cortex; Cyclic AMP; Cyclic GMP; Guinea Pigs; Hippocampus; In Vitro Techniques; Mice; Norepinephrine; Nucleotides, Cyclic; Pentylenetetrazole; Seizures

The objective of the present study was to explore if lesions of the ascending noradrenergic pathways, originating in the locus coeruleus, modulate the cerebral metabolic response to bicuculline-induced seizures in rats. Bilateral noradrenergic lesions were performed by 6-hydroxydopamine injections in the caudal mesencephalon, 12-22 days before seizures were induced in animals ventilated on N2O:O2 (75:25). After 5 min of seizures the brain was frozen in situ and cerebral cortex and hippocampus were sampled for analysis. Labile phosphates, glycolytic metabolites, cyclic nucleotides, and free fatty acids were measured. In another series, lesioned animals were used for measurements of cerebral oxygen consumption. The noradrenergic lesions neither modified the electroencephalographically recorded seizure discharge, nor did they alter cerebral oxygen consumption or cerebral energy state. However, when compared to sham-operated animals, those with noradrenergic lesions had significantly higher (115% and 68%) glycogen concentrations and lower (50% and 52%) cyclic AMP concentrations in cerebral cortex and hippocampus, respectively, demonstrating the marked influence of noradrenergic activity on adenylate cyclase activity and glycogenolysis. The lesions failed to modulate the rise in free fatty acids in the cerebral cortex, or the cyclic GMP concentrations in the cerebral cortex and hippocampus. Thus, increased noradrenergic activity during status epilepticus does not seem responsible for lipolysis or for activation of guanylate cyclase.

Topics: Animals; Bicuculline; Brain; Brain Chemistry; Cyclic AMP; Cyclic GMP; Fatty Acids, Nonesterified; Glycolysis; Locus Coeruleus; Male; Norepinephrine; Rats; Rats, Inbred Strains; Seizures

Topics: Animals; Anticonvulsants; Brain Chemistry; Cyclic AMP; Cyclic GMP; Epilepsy; Humans; Seizures

Topics: Amino Acids; Animals; Anti-Anxiety Agents; Benzodiazepines; Cyclic AMP; Cyclic GMP; Dopamine; Mice; Neurotransmitter Agents; Parasympathetic Nervous System; Seizures; Sympathetic Nervous System

Topics: Animals; Brain Chemistry; Cyclic AMP; Cyclic GMP; Dieldrin; Male; Mice; Nucleotides, Cyclic; Seizures

The previous finding that benzodiazepine-induced changes in cyclic GMP in the cerebellum were poorly correlated with the impairment of motor function has now been extended further. The effects following acute, and during repeated administration of diazepam, quazepam and flurazepam were studied in mice. A 10 day period of daily treatment with 5 mg/kg p.o. was used in these studies. The content of cGMP was significantly reduced (P less than 0.05) during the chronic administration of quazepam and flurazepam except after 10 days for flurazepam. After diazepam, cGMP levels were lower than in control animals but a significant difference was observed only at the sixth and tenth day because a minimal threshold dose was used. Antagonism of pentylenetetrazol-induced convulsions was significantly (P less than 0.05) effective over the 10 day treatment for all drugs. Spontaneous motor activity was reduced by quazepam given for two days and by diazepam given for one day while this measure was unaffected by flurazepam given at the same dose which was effective in the other tests. These results further supported a lack of association between changes of cGMP content in the cerebellum and sedative or muscle relaxant effects of benzodiazepines, whereas the lowering of cGMP levels seemed to parallel effects that are not subject to tolerance such as the antagonism of pentylenetetrazol-induced convulsions.

Topics: Animals; Benzodiazepines; Cerebellum; Cyclic GMP; Male; Mice; Motor Activity; Receptors, Cell Surface; Receptors, Drug; Receptors, GABA-A; Seizures

To characterize further the roles of norepinephrine (NE) and cyclic nucleotides in seizure mechanisms, an examination was made of the effects of several drugs purported to depress noradrenergic influence in the CNS on pentylenetetrazol-induced seizure activity and regulation of cyclic AMP levels in the cerebral cortex and hippocampus in mice. Depletion of brain stores of NE with reserpine or treatment of neonatal mice with 6-hydroxy-dopamine decreased seizure latency and/or threshold and diminished seizure-induced accumulation of cyclic AMP in brain. Propranolol, a beta-adrenergic receptor antagonist, and yohimbine, an alpha 2-adrenergic receptor antagonist, had effects qualitatively similar to reserpine and 6-hydroxy-dopamine, but phentolamine, a mixed alpha-adrenergic antagonist, increased seizure threshold and latency and did not reduce the accumulation of cyclic AMP. None of the drugs tested had any consistent effect on the regulation of cyclic GMP levels in brain during seizures. These data are consistent with the hypothesis that cyclic AMP in brain may be mediating an inhibitory influence of NE on seizure activity.

Topics: Animals; Brain; Cyclic AMP; Cyclic GMP; Drug Interactions; Mice; Norepinephrine; Pentylenetetrazole; Seizures

The effect of halothane on cerebellar control of motor activity and on cerebellar cyclic 3',5'-guanosine monophosphate (cGMP) content was studied in mice. Isoniazide and picrotoxin were used to increase motor activity and induce seizures associated with an increase in cerebellar cGMP content. Halothane markedly decreased the cerebellar cGMP content (by 60 per cent at 0.61 per cent, the concentration at which 50 per cent of mice lost righting reflex) and prevented the isoniazide-induced increase in cGMP content. Halothane, 0.61 per cent, significantly reduced both isoniazide- and picrotoxin-induced motor activity; the ED50 convulsive dose of isoniazide (137.7 +/- 7.04) and of picrotoxin (1.9 +/- 0.2 mg x kg-1, sc) was about three times higher (402.2 +/- 17.9 and 5.8 +/- 0.6 mg x kg-1, sc, respectively) in mice exposed to halothane. In contrast, halothane did not alter the ED50 convulsive dose of strychnine, which has a different site and mechanism of action, blockade of glycine receptors, a mechanism not involving the cerebellar system. These results indicate that halothane has a significant effect on the cerebellar control of motor activity and that cGMP plays an important role in the alteration of cerebellar function by halothane.

Topics: Animals; Cerebellum; Cyclic GMP; Halothane; Isoniazid; Male; Mice; Motor Activity; Picrotoxin; Seizures; Strychnine

The basolateral amygdala of rats was stimulated once daily until three successive fully kindled seizures were elicited. Twenty-four hours after the last seizure the rats were sacrificed by focused microwave irradiation to the head. Tissues from homolateral and contralateral amygdala and cerebral cortex were assayed for cAMP and cGMP content. No significant changes in cyclic nucleotides were measured in the kindled animals. These studies indicate that long term changes in the steady-state level of total tissue cyclic nucleotides do not occur concomitant with the persistently altered excitability associated with kindling of the amygdala.

Topics: Amygdala; Animals; Cyclic AMP; Cyclic GMP; Electric Stimulation; Evoked Potentials; Male; Rats; Seizures

Cerebrospinal fluid levels of gamma-aminobutyric acid (GABA) and cyclic nucleotides were measured in alcoholic and control patients. Alcoholics without seizures had higher GABA levels than either alcoholics with seizures or controls. Levels of cyclic AMP and cyclic GMP in cerebrospinal fluid of controls and alcoholics with and without seizures were not significantly different.

Topics: Alcoholism; Cyclic AMP; Cyclic GMP; gamma-Aminobutyric Acid; Humans; Seizures

The kindling model of experimental epilepsy is characterized by a persistent seizure pattern and long-lasting seizure susceptibility without associated tissue damage. In order to examine the relationship between CSF cyclic nucleotides and epilepsy. CSF cAMP and cGMP were measured before and after kindling, or after electrically induced seizures. Cyclic AMP and cGMP levels in cisternal CSF decreased significantly 1 week after the amygdaloid kindling. This finding suggests decreased levels of brain cAMP and cGMP in this type of epileptogenesis. A slight increase in CSF cyclic nucleotides concentrations was found after triggering both partial and generalized seizures. There was, however, no difference in increase of cAMP and cGMP levels between partial seizure and generalized convulsion, indicating that differences in intensity ictal or postictal events cannot be reflected in the CSF cyclic nucleotide concentrations.

Topics: Amygdala; Animals; Cats; Cyclic AMP; Cyclic GMP; Female; Kindling, Neurologic; Male; Models, Neurological; Seizures

Topics: Aminophylline; Animals; Brain; Cyclic AMP; Cyclic GMP; Electroshock; Rats; Seizures

Topics: Animals; Cyclic GMP; Dibutyryl Cyclic GMP; Drug Interactions; gamma-Aminobutyric Acid; Mice; Oxotremorine; Parasympathomimetics; Picrotoxin; Seizures

Topics: Amygdala; Animals; Cats; Cyclic AMP; Cyclic GMP; Kindling, Neurologic; Male; Seizures

Topics: Animals; Cats; Cyclic AMP; Cyclic GMP; Electric Stimulation; Electroencephalography; Kindling, Neurologic; Probenecid; Seizures

Topics: Animals; Brain; Cyclic AMP; Cyclic GMP; Epilepsy; Humans; Kinetics; Seizures

The effects of pentylenetetrazol on behavior, EEG activity and regional CNS levels of cyclic AMP (cAMP) and cyclic GMP (cGMP) in mice and guinea pigs were studied. Pentylenetetrazol increased cGMP levels in all regions of brain examined (cerebral cortex, hippocampus, striatum and cerebellum) and increased cAMP levels in all regions except striatum. cGMP levels were increased by both sub-convulsant and convulsant doses of pentylenetetrazol. In contrast, cAMP levels were elevated only by concentrations of pentylenetetrazol that produced clinically evident seizures or epileptiform EEG activity. These data indicate that increases in CNS cGMP levels produced by epileptogenic stimuli can occur independently of seizure discharges, whereas accumulation of cAMP requires and is secondary to seizure activity. In conjunction with results of other studies, these data support the hypothesis that cGMP may have a role in seizure genesis and/or propagation, whereas cAMP may be involved in processes that attenuate or terminate seizures.

Topics: Animals; Behavior, Animal; Brain; Cerebellum; Cerebral Cortex; Corpus Striatum; Cyclic AMP; Cyclic GMP; Female; Hippocampus; Mice; Pentylenetetrazole; Seizures

Topics: Animals; Bicuculline; Brain; Cyclic AMP; Cyclic GMP; Dibutyryl Cyclic GMP; Male; Mice; Mice, Inbred C57BL; Seizures

The selectivity and specificity of fenmetozole (DH-524) [2(3,4-dichlorophenoxy-methyl)2-imidazole HCl] as an antagonist of the actions of ethanol were examined. Fenmetozole (15--30 g/kg) reduced ethanol-induced impairment of the aerial righting reflex without changing blood or brain ethanol content, indicating that the antagonistic actions of fenmetozole were not de to change in the pharmacokinetics of ethanol. Since fenmetozole also reduced aerial righting reflex impairment due to phenobarbital, chlordiazepoxide, and halothane, this action of fenmetozole was not specific to ethanol. In mice, both the ethanol-induced increase in locomotor activity at 2.0 g/kg and the decrease caused by 4.0 g/kg were antagonized by fenmetozole. In addition, fenmetozole attenuated the ethanol-induced reduction in cerebellar cyclic guanosine monophosphate (cGMP) content, but the drug also significantly elevated cGMP levels in this tissue when given alone. Fenmetozole did not alter ethanol-induced increases in punished drinking in a conflict test, except at a high dose which alone decreased both punished and unpunished responding. Fenmetozole also failed to precipitate ethanol withdrawal-like reactions when given to physically-dependent, intoxicated rats. Thus, the antagonistic action of fenmetozole against ethanol would not seem to be related to a specific receptor interaction but rather may be the result of a physiological antagonism.

Topics: Acoustic Stimulation; Animals; Behavior, Animal; Brain; Cerebellum; Conflict, Psychological; Cyclic AMP; Cyclic GMP; Ethanol; Humans; Imidazoles; Locomotion; Male; Phenyl Ethers; Rats; Reflex; Seizures; Substance Withdrawal Syndrome

The onset of clonic seizures induced by 3-mercaptopropionic acid (MP) was associated with an approximately 200% increase of cAMP and a 70% elevation of cGMP in the mouse cerebral cortex. There was a further rise of both nucleotides during the subsequent tonic phase of convulsions; cAMP levels reached 400% and cGMP levels 300% of control values. The levels of both nucleotides did not differ from the controls 20 min after the termination of tonic seizures. When MP convulsions were prevented by Na-phenobarbital, the levels of both nucleotides were not different from control concentrations. Phenytoin prevented the tonic extension, but did not affect the clonic seizures. The accumulation of cAMP was markedly reduced (a residual + 40%), whereas the increased levels of cGMP remained unaffected.

Topics: 3-Mercaptopropionic Acid; Animals; Anticonvulsants; Cerebral Cortex; Cyclic AMP; Cyclic GMP; gamma-Aminobutyric Acid; Hybridization, Genetic; Male; Mice; Mice, Inbred ICR; Mice, Inbred Strains; Phenobarbital; Phenytoin; Seizures

Veratridine causes deplorization of excitable cells and produces marked elevation of adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP) levels in incubated slices of mouse cerebral cortex. Phenytoin, carbamazepine, phenobarbital, primidone, phensuximide, methsuximide, alpha-methyl-alpha-phenylsuccinimide, and high concentrations of clonazepam are anticonvulsant drugs that preferentially prevent maximal electroshock seizures (MES) and generalized tonic-clonic convulsions; all these agents inhibit veratridine-induced accumulation of both cyclic AMP and cyclic GMP. In contrast, ethosuximide, trimethadione, valproic acid, and low concentrations of clonazepam are anticonvulsant drugs that act predominantly against Metrazol and absence seizures; these agents are ineffective or inhibit accumulation of only cyclic GMP. The results suggest that inhibition of cyclic AMP and cyclic GMP accumulation in depolarized brain tissue is a molecular neuropharmacological action characteristic of anticonvulsant drugs that have direct effects on cellular membrane function and prevent MES. Anticonvulsant drugs that do not inhibit accumulation of both cyclic AMP and cyclic GMP in depolarized brain tissue preferentially prevent Metrazol and absence seizures and probably exert their effects by altering neurotransmission mechanisms.

Topics: Animals; Anticonvulsants; Brain; Cyclic AMP; Cyclic GMP; Mice; Neurotransmitter Agents; Pentylenetetrazole; Seizures; Time Factors

Topics: Adenosine Triphosphate; Animals; Brain; Cyclic AMP; Cyclic GMP; Electroshock; gamma-Aminobutyric Acid; Glucose; Glycogen; Kinetics; Lactates; Male; Mice; Phenytoin; Phosphocreatine; Purkinje Cells; Seizures

Topics: Animals; Brain; Cerebellum; Cerebral Cortex; Cyclic AMP; Cyclic GMP; gamma-Aminobutyric Acid; Glucose; Isoniazid; Lactates; Male; Mice; Seizures; Valproic Acid

Rats exposed to chronic intake of sodium barbital maintained high circulating levels of barbital in blood and brain and exhibited increased sensitivity ot audiogenic convulsions during the withdrawal period. Levels of gamma-aminobutyric acid (GABA), glutamate, guanosine 3',5'-monophosphate (cyclic GMP) and adenosine 3',5'-monophosphate (cyclic AMP) were measured in selected brain regions after sacrifice with high power microwave inactivation. Cyclic GMP during chronic barbital administration was significantly lower than controls in most brain regions, especially the hindbrain. During the withdrawal period cyclic GMP in the cerebellum was significantly increased, while returning at least to control levels in all other regions. GABA throughout the brain tended to be reduced during barbital dependence, while cyclic AMP and glutamate levels remained unchanged in all groups. These results indicate a possible role for cyclic GMP in the mediation of the central nervous system response during barbiturate dependence and withdrawal.

Topics: Acoustic Stimulation; Animals; Barbital; Barbiturates; Brain; Cyclic AMP; Cyclic GMP; gamma-Aminobutyric Acid; Glutamates; Humans; Male; Rats; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

Convulsant doses of pentylenetetrazol (100 mg/kg) increase levels of both cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP in mouse cerebral cortex and hippocampus. In animals pretreated with reserpine, propranolol, or aminophylline, pentylenetetrazol seizures were more severe, cyclic AMP elevations were attenuated or blocked, and cyclic GMP increases were unaffected or augmented. These data indicate that norepinephrine, adenosine, and perhaps other biogenic amines have a regulatory effect on cyclic AMP, but not cyclic GMP, levels in epileptic brain. An increased level of cyclic AMP in brain tissue may have an antiepileptic effect leading to seizure attenuation or termination. By contrast, elevated levels of cyclic GMP may have an epileptogenic effect in initiating or maintaining seizure activity.

Topics: Aminophylline; Animals; Brain; Cyclic AMP; Cyclic GMP; Female; Mice; Pentylenetetrazole; Propranolol; Reserpine; Seizures

Topics: Animals; Anticonvulsants; Cerebellum; Cyclic GMP; Male; Organophosphorus Compounds; Rats; Seizures; Soman

Topics: Animals; Brain; Bucladesine; Butyrates; Cyclic GMP; Dose-Response Relationship, Drug; Exploratory Behavior; Male; Mice; Motor Activity; Seizures

Topics: Amphetamine; Animals; Atropine; Cerebellum; Cyclic AMP; Cyclic GMP; Diazepam; Female; Harmaline; In Vitro Techniques; Mice; Oxotremorine; Pentylenetetrazole; Reserpine; Seizures; Stress, Physiological

Topics: Animals; Atropine; Brain; Cerebellum; Cerebral Cortex; Cyclic AMP; Cyclic GMP; Diazepam; Dose-Response Relationship, Drug; Drug Interactions; GABA Antagonists; Male; Organophosphates; Organophosphorus Compounds; Rats; Receptors, Muscarinic; Seizures

Topics: Animals; Brain; Cerebellum; Cerebral Cortex; Corpus Striatum; Cyclic AMP; Cyclic GMP; Ethosuximide; Female; Hippocampus; Mice; Pentylenetetrazole; Phenobarbital; Phenytoin; Seizures; Thalamus

Topics: Cerebellum; Cerebral Cortex; Chlordiazepoxide; Convulsants; Cyclic AMP; Cyclic GMP; Dose-Response Relationship, Drug; Harmaline; Kinetics; Prostaglandins E; Seizures; Tetrazoles

Topics: Animals; Cerebellum; Cyclic AMP; Cyclic GMP; Male; Pentylenetetrazole; Prostaglandins E; Rats; Seizures; Tremor

Topics: Cyclic AMP; Cyclic GMP; Humans; Nervous System Diseases; Probenecid; Seizures