dizocilpine-maleate has been researched along with Body-Weight* in 64 studies
1 review(s) available for dizocilpine-maleate and Body-Weight
1 trial(s) available for dizocilpine-maleate and Body-Weight
63 other study(ies) available for dizocilpine-maleate and Body-Weight
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The influence of temperature on adult zebrafish sensitivity to pentylenetetrazole.
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 | 2017 |
Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open-field activity in Sprague-Dawley rats.
Most antidepressants inhibit monoamine reuptake. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) act on the 5-HT transporter (SERT) whereas norepinephrine-dopamine reuptake inhibitors (NDRIs) act on the norepinephrine and dopamine transporters. Epidemiological reports link SSRI use during pregnancy to an increased prevalence of autism spectrum disorder (ASD). We previously showed that perinatal exposure to the SSRI citalopram (CIT) results in rodent offspring that exhibit a number of behaviors consistent with an ASD-like phenotype. The present study examined the effect of perinatal exposure to CIT (at a lower dose), another SSRI, fluoxetine (FLX), and an NDRI, bupropion (BUP). Gravid Sprague-Dawley rats were subcutaneously injected twice per day (6h apart) with 5mg/kg CIT, 5mg/kg FLX, 15mg/kg BUP, or saline (SAL) from embryonic day (E) 6-21, and directly to the pups from postnatal day (P) 1-20. As adults, one male/female from each litter was given one of a series of tests. Both SSRI-exposed groups showed spatial learning deficits in Morris and radial water mazes, increased marble burying, increased acoustic startle, hypoactivity, and attenuated activity to the stimulating effect of the NMDA-R antagonist MK-801. The BUP-exposed group showed a reduction in elevated zero-maze quadrant entries and increased stimulated open-field activity following (+)-amphetamine challenge. These results reinforce concern about the use of antidepressants during pregnancy and highlight how the two classes of drugs produce different constellations of effects with more effects associated with the SSRIs. Further investigation into how antidepressants alter brain development leading to enduring adverse neurobehavioral effects is warranted. Topics: Acoustic Stimulation; Age Factors; Animals; Antidepressive Agents; Anxiety; Body Weight; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Exploratory Behavior; Female; Learning; Male; Maze Learning; Memory; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Reflex, Startle; Social Behavior | 2017 |
NMDA Receptors as Potential Therapeutic Targets in Diabetic Nephropathy: Increased Renal NMDA Receptor Subunit Expression in Akita Mice and Reduced Nephropathy Following Sustained Treatment With Memantine or MK-801.
N-methyl-d-aspartate (NMDA) receptors are expressed throughout the kidney, and the abundance of these receptors and some of their endogenous agonists are increased in diabetes. Moreover, sustained activation of podocyte NMDA receptors induces Ca(2+) influx, oxidative stress, loss of slit diaphragm proteins, and apoptosis. We observed that NMDA receptor subunits and their transcripts are increased in podocytes and mesangial cells cultured in elevated glucose compared with controls. A similar increase in NMDA subunits, especially NR1, NR2A, and NR2C, was observed in glomeruli and tubules of Akita mice. Sustained continuous treatment with the strong NMDA receptor antagonist dizocilpine (MK-801) for 28 days starting at 8 weeks of age reduced 24-h albumin excretion and mesangial matrix expansion and improved glomerular ultrastructure in Akita mice. MK-801 did not alleviate reduced Akita mouse body weight and had no effect on kidney histology or ultrastructure in DBA/2J controls. The structurally dissimilar NMDA antagonist memantine also reduced diabetic nephropathy, although it was less effective than MK-801. Inhibition of NMDA receptors may represent a valid therapeutic approach to reduce renal complications of diabetes, and it is possible to develop well-tolerated agents with minimal central nervous system effects. Two such agents, memantine and dextromethorphan, are already in widespread clinical use. Topics: Animals; Body Weight; Diabetic Nephropathies; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Kidney; Kidney Glomerulus; Kidney Tubules; Memantine; Mesangial Cells; Mice; Podocytes; Receptors, N-Methyl-D-Aspartate | 2016 |
Perinatal exposure to the selective serotonin reuptake inhibitor citalopram alters spatial learning and memory, anxiety, depression, and startle in Sprague-Dawley rats.
Selective serotonin reuptake inhibitors (SSRIs) block the serotonin (5-HT) reuptake transporter (SERT) and increase synaptic 5-HT. 5-HT is also important in brain development; hence when SSRIs are taken during pregnancy there exists the potential for these drugs to affect CNS ontogeny. Prenatal SSRI exposure has been associated with an increased prevalence of autism spectrum disorder (ASD), and peripheral 5-HT is elevated in some ASD patients. Perinatal SSRI exposure in rodents has been associated with increased depression and anxiety-like behavior, decreased sociability, and impaired learning in the offspring, behaviors often seen in ASD. The present study investigated whether perinatal exposure to citalopram causes persistent neurobehavioral effects. Gravid Sprague-Dawley rats were assigned to two groups and subcutaneously injected twice per day with citalopram (10mg/kg; Cit) or saline (Sal) 6h apart on embryonic day (E)6-21, and then drug was given directly to the pups after delivery from postnatal day (P)1-20. Starting on P60, one male/female from each litter was tested in the Cincinnati water maze (CWM) and open-field before and after MK-801. A second pair from each litter was tested in the Morris water maze (MWM) and open-field before and after (+)-amphetamine. A third pair was tested as follows: elevated zero-maze, open-field, marble burying, prepulse inhibition of acoustic startle, social preference, and forced swim. Cit-exposed rats were impaired in the MWM during acquisition and probe, but not during reversal, shift, or cued trials. Cit-exposed rats also showed increased marble burying, decreased time in the center of the open-field, decreased latency to immobility in forced swim, and increased acoustic startle across prepulse intensities with no effects on CWM. The results are consistent with citalopram inducing several ASD-like effects. The findings add to concerns about use of SSRIs during pregnancy. Further research on different classes of antidepressants, dose-effect relationships, timing of exposure periods, and mechanisms for these effects are needed. It is also important to balance the effects described here against the effects of the disorders for which the drugs are given. Topics: Age Factors; Amphetamines; Animals; Animals, Newborn; Anxiety; Body Weight; Citalopram; Depression; Dizocilpine Maleate; Exploratory Behavior; Female; Male; Maze Learning; Neuroprotective Agents; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Sensory Gating; Sex Factors; Spatial Learning; Swimming | 2016 |
Ketogenic diet reverses behavioral abnormalities in an acute NMDA receptor hypofunction model of schizophrenia.
Topics: 3-Hydroxybutyric Acid; Animals; Body Weight; Diet, Ketogenic; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glucose; Humans; Male; Mental Disorders; Mice; Mice, Inbred C57BL; Receptors, N-Methyl-D-Aspartate; Schizophrenia | 2015 |
Impaired working memory by repeated neonatal MK-801 treatment is ameliorated by galantamine in adult rats.
Early life blockade of the NMDA receptor by using MK-801, a non-competitive NMDA receptor antagonist, induces behavioral changes that mimic several features of schizophrenia. In the current study, we first examined the effects of neonatal MK-801 treatment in male Sprague-Dawley rats on locomotor activity, prepulse inhibition and spatial working memory in adolescence (postnatal day 35, PND35) and adulthood (PND63). Next, we investigated the effects of an acetylcholinesterase inhibitor, galantamine, on working memory deficits induced by MK-801 treatment. Rats were treated with either saline or MK-801 (0.25mg/kg twice daily) at PND 5-14, and the long-term behavioral effects were investigated. MK-801 treated rats showed moderate working memory impairments in adolescence but a pronounced deficit in adulthood. However, locomotion and prepulse inhibition at two life stages were not affected by this treatment. Systemic administration of galantamine (1mg/kg) 30 min before each training session significantly improved neonatal MK-801-induced working memory deficits in adulthood. In conclusion, these results suggest that the neonatal MK-801 treatment-induced selective working memory deficit is related to a change in brain cholinergic systems. Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Cholinesterase Inhibitors; Dizocilpine Maleate; Female; Galantamine; Locomotion; Male; Memory, Short-Term; Pregnancy; Rats; Rats, Sprague-Dawley; Spatial Behavior | 2014 |
White matter injuries induced by MK-801 in a mouse model of schizophrenia based on NMDA antagonism.
The etiology of schizophrenia (SZ) is complex and largely unknown. Neuroimaging and postmortem studies have suggested white matter disturbances in SZ. In the present study, we tested the white matter deficits hypothesis of SZ using a mouse model of SZ induced by NMDA receptor antagonist MK-801. We found that mice with repeated chronic MK-801 administration showed increased locomotor activity in the open field test, less exploration of a novel environment in the hole-board test, and increased anxiety in the elevated plus maze but no impairments were observed in coordination or motor function on accelerating rota-rod. The total white matter volume and corpus callosum volume in mice treated with MK-801 were significantly decreased compared to control mice treated with saline. Myelin basic protein and 2', 3'-cyclic nucleotide 3'-phosphodiesterase were also significantly decreased in the mouse model of SZ. Furthermore, we observed degenerative changes of myelin sheaths in the mouse model of SZ. These results provide further evidence of white matter deficits in SZ and indicate that the animal model of SZ induced by MK-801 is a useful model to investigate mechanisms underlying white matter abnormalities in SZ. Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Behavior, Animal; Blotting, Western; Body Weight; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Immunoenzyme Techniques; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Motor Activity; Myelin Basic Protein; Nerve Fibers, Myelinated; Real-Time Polymerase Chain Reaction; Receptors, N-Methyl-D-Aspartate; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Schizophrenia; White Matter | 2014 |
Effects of NMDA receptor blockade during the early development period on the retest performance of adult Wistar rats in the elevated plus maze.
The elevated plus maze (EPM) is an animal model of anxiety used to test the effects of anxioselective drugs. The loss of the anxiolytic effect of drugs during the second exposure to the EPM is called the "one trial tolerance" (OTT) phenomenon. The present study was designed to investigate the relationship between the OTT phenomenon and N-methyl-D-aspartate (NMDA) receptor blockade in the early developmental period of rats. NMDA receptor blockade was accomplished using MK-801 treatment given between postnatal days 20-30. Beginning on postnatal day 20, the rats were subcutaneously injected with MK-801 twice a day at the nape of the neck for a period of 10 days (0.25 mg/kg). Increased open arm exploration was observed in MK-801-treated rats during trial 1 (p = 0.001) and trial 2 (p = 0.003). The rats spent less time in the closed arms as compared to the saline animals in trial 1 (p = 0.006), and this time decreased further in trial 2 (p = 0.02). The fecal boli of the MK-801 group was decreased in trial 1 as compared to the saline group (p = 0.01), but was not significantly different in trial 2 (p = 0.08). In conclusion, NMDA receptor blockade using MK-801 produced an anxiolytic-like effect in trials 1 and 2. Furthermore, OTT was not affected by NMDA receptor blockade. Topics: Animals; Body Weight; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Maze Learning; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate | 2013 |
A "double hit" murine model for schizophrenia shows alterations in the structure and neurochemistry of the medial prefrontal cortex and the hippocampus.
Both alterations in neurodevelopment and aversive experiences during childhood and adolescence seem important risk factors for schizophrenia. Animal models reproducing these alterations mimic some of the symptoms, constituting a valid approach to study the etiopathology of this disorder. Among these models, the perinatal injection of N-methyl-d-aspartate receptor antagonists and the postweaning social isolation rearing are among the most widely used. Our aim is to combine them in a "double hit" model, which should produce a wider spectrum of alterations. Lister Hooded rats have been subjected to a single injection of MK-801 at postnatal day 7 and socially isolated from postweaning to adulthood. These animals presented increased body weight gain and volume reductions in their medial prefrontal cortex (mPFC) and hippocampus. They also showed an increased number of activated pyramidal neurons and alterations in the numbers of parvalbumin and calbindin expressing interneurons in the mPFC. The expressions of the polysialylated form of the neural cell adhesion molecule and GAD67 are decreased in the mPFC. The mRNA level of calbindin was decreased, while that of calretinin was increased in the mPFC. The mRNA level of ERbB4, a gene associated to schizophrenia, was also altered in this region. All these structural and neurochemical alterations, specially in cortical inhibitory circuits, are similar to those found in schizophrenic patients and are more numerous than in each of the single models. Consequently, the present "double hit" model may be a better tool to study the neurobiological basis of schizophrenia and to explore new therapeutic approaches. Topics: Animals; Animals, Newborn; Body Weight; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Gene Expression Regulation; Hippocampus; Male; Nerve Tissue Proteins; Neural Cell Adhesion Molecules; Prefrontal Cortex; Pregnancy; Proto-Oncogene Proteins c-fos; Rats; Schizophrenia; Social Isolation | 2013 |
Spontaneous polydipsia in animals treated subchronically with MK-801.
Topics: Age Factors; Amphetamine; Animals; Animals, Newborn; Body Weight; Central Nervous System Stimulants; Cognition Disorders; Cohort Studies; Disease Models, Animal; Dizocilpine Maleate; Drinking; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Food Deprivation; Male; Motor Activity; Polydipsia; Random Allocation; Rats; Rats, Sprague-Dawley | 2013 |
Distinct periods of developmental sensitivity to the effects of 3,4-(±)-methylenedioxymethamphetamine (MDMA) on behaviour and monoamines in rats.
Previous findings showed allocentric and egocentric learning deficits in rats after MDMA treatment from postnatal days (PD) 11-20 but not after treatment from PD 1-10. Shorter treatment periods (PD 1-5, 6-10, 11-15, or 16-20) resulted in allocentric learning deficits averaged across intervals but not for any interval individually and no egocentric learning deficits individually or collectively. Whether this difference was attributable to treatment length or age at the start of treatment was unclear. In the present experiment rat litters were treated on PD 1-10, 6-15, or 11-20 with 0, 10, or 15 mg/kg MDMA q.i.d. at 2-h intervals. Two male/female pairs/litter received each treatment. One pair/litter received acoustic startle with prepulse inhibition, straight channel swimming, Cincinnati water maze (CWM), and conditioned fear in a latent inhibition paradigm. The other pair/litter received locomotor activity, straight channel swimming, Morris water maze (MWM), and locomotor activity retest with MK-801 challenge. MDMA impaired CWM learning following PD 6-15 or 11-20 exposure. In MWM acquisition, all MDMA-treated groups showed impairment. During reversal and shift, the PD 6-15 and PD 11-20 MDMA-treated groups were significantly impaired. Reductions in locomotor activity were most evident after PD 6-15 treatment while increases in acoustic startle were most evident after PD 1-10 treatment. After MK-801 challenge, MDMA-treated offspring showed less locomotion compared to controls. Region-specific changes in brain monoamines were also observed but were not significantly correlated with behavioural changes. The results show that PD 11-20 exposure to MDMA caused the largest long-term cognitive deficits followed by PD 6-15 exposure with PD 1-10 exposure least affected. Other effects, such as those upon MK-801-stimulated locomotion showed greatest effects after PD 1-10 MDMA exposure. Hence, each effect has a different window of developmental susceptibility. Topics: Acoustic Stimulation; Aging; Animals; Animals, Newborn; Behavior, Animal; Biogenic Monoamines; Body Weight; Conditioning, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Fear; Female; Hallucinogens; Inhibition, Psychological; Male; Maze Learning; Mortality; Motor Activity; N-Methyl-3,4-methylenedioxyamphetamine; Rats; Rats, Sprague-Dawley; Reaction Time; Reflex, Startle; Swimming | 2012 |
Increased expression of the Vesicular Glutamate Transporter-1 (VGLUT1) in the prefrontal cortex correlates with differential vulnerability to chronic stress in various mouse strains: effects of fluoxetine and MK-801.
Major depression is a chronic psychiatric illness that is highly prevalent and disabling. The available medications are ineffective for many patients suggesting that differents molecular pathways could be specifically altered in the unresponsive patients. Recently, the glutamatergic system has emerged as a target in the research on depression and acute NMDA receptor blockade has been shown to produce strong antidepressant effects. We have studied the adaptations of four mice strains (C57BL/6, DBA/2, C3H and BALB/c) to a chronic unpredictable stress protocol, a widely used model of depression in rodents. BALB/c mice displayed strikingly different behavioral and neurochemical adaptations compared to the other strains tested, suggesting that different molecular pathways are involved in their specific vulnerability. They became hyperactive during the dark period, anhedonic-like and displayed no alterations in the tail suspension test (TST). After chronic stress, only the BALB/c displayed an increased frontocortical VGLUT1 expression which is suggestive of a dysregulation of their prefrontal glutamatergic system, and no BDNF mRNA alteration, although the acute stress modulation of this mRNA is similar to the other strains. Chronic administration of an antagonist of NMDA receptors, MK-801, induced antidepressant-like effects in the TST for stressed BALB/c, but was ineffective for the hyperactivity and anhedonia-like behavior, in contrast to fluoxetine. Chronic MK-801 was totally inactive on the behavior of stressed C57BL/6 mice. MK-801, but not fluoxetine, inhibited the VGLUT1 prefrontal increase in BALB/c. Fluoxetine increased VGLUT1 and BDNF mRNA expression in the hippocampus of the C57BL/6 but not in the BALB/c strain, suggesting a different reactivity in-between strain to both stress and antidepressant. Interestingly enough, the BDNF or VGLUT1 increase is not necessary to reverse the stress induced behavioral alterations in our experimental settings. This observation supports the conclusion that BDNF and VGLUT1 are depressive state markers, but not involved in its etiology. Finally, there is a substantial similarity between the phenotypes that are observed in the BALB/c mice and endogenous depression in humans, as well as between C57BL/6 mice and atypical depression. To have a better understanding of the variability of depression etiologies in human, and the implication of the glutamatergic system, it may be suggested that future animal studies in the mouse Topics: Analysis of Variance; Animals; Antibodies; Antidepressive Agents; Body Weight; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Dizocilpine Maleate; Fluoxetine; Food Preferences; Gene Expression Regulation; Hair; Hindlimb Suspension; Iodine Radioisotopes; Male; Mice; Mice, Inbred Strains; Motor Activity; Neuroprotective Agents; Prefrontal Cortex; Radioligand Assay; RNA, Messenger; Species Specificity; Stress, Psychological; Sucrose; Time Factors; Vesicular Glutamate Transport Protein 1 | 2012 |
Long-term behavioral and NMDA receptor effects of young-adult corticosterone treatment in BDNF heterozygous mice.
Psychiatric illnesses, such as schizophrenia, are most likely caused by an interaction between genetic predisposition and environmental factors, including stress during development. The neurotrophin, brain-derived neurotrophic factor (BDNF) has been implicated in this illness as BDNF levels are decreased in the brain of patients with schizophrenia. The aim of the present study was to assess the combined effect of reduced BDNF levels and postnatal stress, simulated by chronic young-adult treatment with the stress hormone, corticosterone. From 6 weeks of age, female and male BDNF heterozygous mice and their wild-type controls were chronically treated with corticosterone in their drinking water for 3 weeks. At 11 weeks of age, male, but not female BDNF heterozygous mice treated with corticosterone exhibited a profound memory deficit in the Y-maze. There were no differences between the groups in baseline prepulse inhibition (PPI), a measure of sensorimotor gating, or its disruption by treatment with MK-801. However, an increase in startle caused by MK-801 treatment was absent in male, but not female BDNF heterozygous mice, irrespective of corticosterone treatment. Analysis of protein levels of the NMDA receptor subunits NR1, NR2A, NR2B and NR2C, showed a marked increase of NR2B levels in the dorsal hippocampus of male BDNF heterozygous mice treated with corticosterone. In the ventral hippocampus, significantly reduced levels of NR2A, NR2B and NR2C were observed in male BDNF heterozygous mice. The NMDA receptor effects in hippocampal sub-regions could be related to the spatial memory deficits and the loss of the effect of MK-801 on startle in these mice, respectively. No significant changes in NMDA receptor subunit levels were observed in any of the female groups. Similarly, no significant changes in levels of BDNF or its receptor, TrkB, were found other than the expected reduced levels of BDNF in heterozygous mice. In conclusion, the data show differential interactive effects of reduced levels of BDNF expression and corticosterone treatment on spatial memory and startle in male and female mice, accompanied by significant, but region-specific changes in NMDA receptor subunit levels in the dorsal and ventral hippocampus. These results could be important for our understanding of the interaction of neurodevelopmental stress and BDNF deficiency in cognitive and anxiety-related symptoms of psychiatric illnesses, such as schizophrenia. Topics: Animals; Behavior, Animal; Blotting, Western; Body Weight; Brain-Derived Neurotrophic Factor; Corticosterone; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Heterozygote; Hippocampus; Male; Maze Learning; Memory; Memory, Short-Term; Mice; Mice, Inbred C57BL; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Sex Characteristics | 2012 |
The effect of neonatal N-methyl-D-aspartate receptor blockade on exploratory and anxiety-like behaviors in adult BALB/c and C57BL/6 mice.
N-methyl-D-aspartate (NMDA) receptors play an important role in brain maturation and developmental processes. In our study, we evaluated the effects of neonatal NMDA receptor blockade on exploratory locomotion and anxiety-like behaviors of adult BALB/c and C57BL/6 mice. In this study, NMDA receptor hypofunction was induced 7-10 days after birth using MK-801 in BALB/c and C57BL/6 mice (0.25mg/kg twice a day for 4 days via intraperitoneal injection). The open-field (OF) and elevated plus maze (EPM) tests were used to evaluate exploratory locomotion and anxiety-like behaviors. In the OF, BALB/c mice spent less time in the center of the field (p<0.05) and had less vertical locomotor activity (p<0.01) compared to C57BL/6 mice. In BALB/c mice, MK-801 caused a decrease in vertical and horizontal locomotor activity in the OF test, compared to the control group (p<0.05). In C57BL/6 mice, MK-801 treatment increased horizontal locomotor activity and decreased time spent in the center in the OF test (p<0.05). In the EPM, the number of open-arm entries, the percentage of open-arm time (p<0.01) and total arm entries (p<0.05) were lower in BALB/c mice compared to C57BL/6 mice. In BALB/c mice, MK-801 caused an increase in the percentage of open-arm time compared to the control group (p<0.05). In C57BL/6 mice, MK-801 caused a decrease in the percentage of open-arm time compared to the control group (p<0.05). MK-801 decreased exploratory and anxiety-like behaviors in BALB/c mice. In contrast, MK-801 increased exploratory and anxiety-like behaviors in C57BL/6 mice. In conclusion, hereditary factors may play an important role in neonatal NMDA receptor blockade-induced responses. Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Anxiety; Body Weight; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Exploratory Behavior; Maze Learning; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Reaction Time; Receptors, N-Methyl-D-Aspartate; Species Specificity | 2012 |
The investigation of neonatal MK-801 administration and physical environmental enrichment on emotional and cognitive functions in adult Balb/c mice.
N-methyl-D-aspartate (NMDA) receptors play an important role in brain maturation and developmental processes. It is known that growing up in an enriched environment has effects on emotional and cognitive performance. In our study, we evaluated the effects of physically enriched environment on the emotional and cognitive functions of the adult brain in the setting of previous NMDA receptor hypoactivity during the critical developmental period of the nervous system. In this study, NMDA receptor blockade was induced 5-10 days postnatally (PD5-10) using MK-801 in mice Balb/c (twice a day 0.25 mg/kg, for 5 days, intraperitoneal). MK-801 was given to developing mice living in a standard (SE) and an enrichment environment (EE) and once the animals reached adulthood, emotional behaviors were evaluated using an open field test (OF) and an elevated plus maze (EPM) test whereas cognitive processes were evaluated using the Morris water-maze (MWM). The EE group showed decreased locomotor activity (p<0.05) in the OF and increased exploratory behaviour (p<0.01) and decreased fear of heights/anxiety-like behaviour (p<0.05) in the EPM test. The EE had positive effects on spatial learning in the MWM (p<0.05). Blockade of the NMDA receptor increased the fear of height (p<0.05), decreased exploratory behaviour and locomotor activity (p<0.001). Also, it led to decreased spatial learning (p<0.05). The decreases in spatial learning and exploratory behaviours and the increase in fear of heights/anxiety-like behaviour with NMDA receptor blockade was not reversed by EE. NMDA receptor blockade during the critical period of development led to deterioration in the emotional and cognitive processes during adulthood. An enriched environmental did not reverse the deleterious effects of the NMDA receptor blockade on emotional and cognitive functions. Topics: Animals; Animals, Newborn; Anxiety; Body Weight; Brain; Cognition; Critical Period, Psychological; Dizocilpine Maleate; Emotions; Environment; Exploratory Behavior; Growth; Learning; Male; Maze Learning; Memory; Mice; Mice, Inbred BALB C; Motor Activity; Neuroprotective Agents; Swimming | 2012 |
Individual differences in maternal response to immune challenge predict offspring behavior: contribution of environmental factors.
Maternal infection during pregnancy elevates risk for schizophrenia and related disorders in offspring. Converging evidence suggests the maternal inflammatory response mediates the interaction between maternal infection, altered brain development, and behavioral outcome. The extent to which individual differences in the maternal response to immune challenge influence the development of these abnormalities is unknown. The present study investigated the impact of individual differences in maternal response to the viral mimic polyinosinic:polycytidylic acid (poly I:C) on offspring behavior. We observed significant variability in body weight alterations of pregnant rats induced by administration of poly I:C on gestational day 14. Furthermore, the presence or absence of maternal weight loss predicted MK-801 and amphetamine stimulated locomotor abnormalities in offspring. MK-801 stimulated locomotion was altered in offspring of all poly I:C treated dams; however, the presence or absence of maternal weight loss resulted in decreased and modestly increased locomotion, respectively. Adult offspring of poly I:C treated dams that lost weight exhibited significantly decreased amphetamine stimulated locomotion, while offspring of poly I:C treated dams without weight loss performed similarly to vehicle controls. Social isolation and increased maternal age predicted weight loss in response to poly I:C but not vehicle injection. In combination, these data identify environmental factors associated with the maternal response to immune challenge and functional outcome of offspring exposed to maternal immune activation. Topics: Age Factors; Amphetamine; Analysis of Variance; Animals; Animals, Newborn; Antiviral Agents; Behavior, Animal; Body Weight; Central Nervous System Stimulants; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Individuality; Locomotion; Male; Poly I-C; Predictive Value of Tests; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Weight Gain; Weight Loss | 2011 |
N-methyl-d-aspartic acid receptors are altered by stress and alcohol in Wistar-Kyoto rat brain.
Previous studies have shown that the Wistar-Kyoto (WKY) rat strain is more sensitive to stressors and consumes significant quantities of alcohol under basal as well as stressful conditions when compared to other strains. Given that the glutamate neurotransmitter system has been implicated in depression and addiction, the goals of the present study were to investigate the effects of stress and stress-alcohol interactions on N-methyl-d-aspartate (NMDA) receptors in the rat brain. Thus this study measured the binding of [(3)H] MK-801 to NMDA receptors in the prefrontal cortex (PFC), caudate putamen (CPu), nucleus accumbens (NAc), hippocampus (HIP) and basolateral amygdala (BLA) in WKY rats in comparison to the Wistar (WIS) rat strain. Our results suggested that while voluntary alcohol consumption did not alter NMDA receptors in the PFC, CPu or NAc in either rat strain, it increased NMDA receptors in the HIP and BLA in both strains. In contrast, chronic stress increased NMDA receptors in the PFC, CPu, NAc in WKY rats but not in WIS rats. Chronic stress also decreased NMDA receptors in the HIP and increased NMDA receptors in the BLA in both strains. Alcohol co-treatment with stress increased NMDA receptors in the PFC, CPu and NAc in WKY rats but not in WIS rats. Interestingly, while alcohol co-treatment did not reverse stress induced decreases in NMDA receptors in the HIP, it reduced the binding of NMDA receptors in the BLA to control levels in both strains. Thus it appears that NMDA receptors in the PFC, CPu and NAc may be more sensitive to the effects of stress and could be implicated in the stress-induced alcohol consumption behavior seen in WKY rats. In contrast, NMDA receptors in the HIP and BLA may reflect an adaptive response and may not be responsible for the stress susceptible phenotype of the WKY rat strain. Topics: Adaptation, Physiological; Alcohol Drinking; Amygdala; Animals; Body Weight; Brain; Disease Susceptibility; Dizocilpine Maleate; Ethanol; Hippocampus; Male; Neostriatum; Nucleus Accumbens; Organ Specificity; Prefrontal Cortex; Rats; Rats, Inbred WKY; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Species Specificity; Stress, Physiological; Stress, Psychological | 2010 |
Intrahippocampal administration of an NMDA-receptor antagonist impairs spatial discrimination reversal learning in weanling rats.
Systemic administration of MK-801, an NMDA-receptor antagonist, impairs reversal learning in weanling rats [Chadman, K.K., Watson, D.J., & Stanton, M.E. (2006). NMDA-receptor antagonism impairs reversal learning in developing rats. Behavioral Neuroscience, 120(5), 1071-1083]. The brain systems responsible for this effect are not known in either adult or young animals. This study tested the hypothesis that hippocampal NMDA receptors are engaged in weanling-age rats during spatial discrimination reversal training in a T-maze. In Experiment 1, 26-day-old Long-Evans rats (P26) showed a dose-related impairment on this task following bilateral intrahippocampal administration of either 2.5 or 5.0microg MK-801 or saline vehicle during the reversal training phase only. In Experiment 2, P26 rats were trained on the same task, but received intrahippocampal MK-801 (2.5microg) during acquisition, reversal, both, or neither. MK-801 failed to impair acquisition, ruling out nonspecific "performance effects" of the drug. MK-801 impaired reversal irrespective of drug treatment during acquisition. NMDA-receptor antagonism in the hippocampus is sufficient to account for the previously reported effects of systemic MK-801 on reversal of T-maze position discrimination. Topics: Analysis of Variance; Animals; Body Weight; Catheterization; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Hippocampus; Male; Maze Learning; Rats; Rats, Long-Evans; Reaction Time; Receptors, N-Methyl-D-Aspartate; Reversal Learning; Space Perception | 2009 |
Spatial discrimination reversal learning in weanling rats is impaired by striatal administration of an NMDA-receptor antagonist.
The striatum plays a major role in both motor control and learning and memory, including executive function and "behavioral flexibility." Lesion, temporary inactivation, and infusion of an N-methyl-d-aspartate (NMDA)-receptor antagonist into the dorsomedial striatum (dmSTR) impair reversal learning in adult rats. Systemic administration of MK-801 disrupts reversal learning in developing rats, as reported in an earlier work by Chadman et al., but it is not known whether NMDA-receptor function within the dmSTR plays a role in this effect. In Experiment 1, reversal learning was dose-dependently impaired following bilateral dmSTR administration of MK-801 (either 2.5 or 5.0 microg) only during the reversal phase relative to saline in postnatal day (P) 26 rats. In Experiment 2, separate groups of P26 rats were trained on the same reversal learning task, but were administered bilateral dmSTR infusions during acquisition only (MK-SAL), reversal only (SAL-MK), both phases (MK-MK), or neither phase (SAL-SAL). The MK-801 effect was specific to the reversal training phase. The drug did not alter acquisition of the initial discrimination. Analysis of the pattern of errors indicates that dmSTR MK-801 treatment increased perseveration of the choice response trained in acquisition. NMDA receptors in the dmSTR play a role in reversal learning in the weanling rat. Topics: Analysis of Variance; Animals; Animals, Newborn; Body Weight; Corpus Striatum; Discrimination Learning; Dizocilpine Maleate; Female; Male; Maze Learning; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Reversal Learning; Space Perception | 2009 |
Evaluation of NMDA receptor models of schizophrenia: divergences in the behavioral effects of sub-chronic PCP and MK-801.
The hypothesis of hypo-functionality of NMDA receptors in schizophrenia originates from the observation that administration of the NMDA antagonist phencyclidine (PCP) induces psychotic states that closely resemble schizophrenic symptoms and that persist after drug discontinuation. A large number of animal studies have used PCP and the NMDA antagonist dizocilpine (MK-801) almost interchangeably to model schizophrenia. However, PCP interacts with pharmacological targets other than NMDA receptors that are not affected by MK-801. In addition, although acute administration of either compound produces similar effects in animals, there is little information whether withdrawal from chronic MK-801 causes behavioral deficits that mimic schizophrenia symptoms as in the case of PCP. To clarify this issue, we compared the following behaviors in rats subjected to withdrawal from sub-chronic administration (2 x 7 days) of either PCP (5 mg/kg, i.p.) or MK-801 (0.5 mg/kg, i.p.): (1) working memory in a variable-delayed alternation task in a T-maze, (2) social interaction, and (3) motor activity in response to a (a) novel environment, (b) mild stressor, and (c) d-amphetamine challenge. Withdrawal from sub-chronic PCP caused a delay-dependent impairment of working memory, reduced social interaction and enhanced d-amphetamine-induced motor activity. These results were not replicated in animals sub-chronically treated with MK-801, which displayed only a slight decrease in social interaction. These data suggest that pharmacological antagonism at NMDA receptors is not sufficient to explain the full spectrum of PCP psychotomimetic properties. Topics: Animals; Body Weight; Disease Models, Animal; Dizocilpine Maleate; Male; Memory, Short-Term; Motor Activity; Phencyclidine; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Social Behavior; Substance Withdrawal Syndrome | 2009 |
Electrophysiological effects of dizocilpine (MK-801) in adult rats exposed to ethanol during adolescence.
Despite evidence showing persistent changes in N-methyl-D-aspartate (NMDA)-receptor function following ethanol (EtOH) exposure, the contribution of NMDA systems to the long-term neurophysiological consequences of adolescent EtOH exposure is unclear. The aims of this study were the following: (1) to determine whether adolescent EtOH exposure produces neurophysiological changes after a prolonged withdrawal period in adult rats and (2) to assess protracted alterations in neurophysiological responses to the NMDA antagonist MK-801 in adult rats exposed to EtOH during adolescence.. Adolescent male Wistar rats were exposed to EtOH vapor for 12 h/d for 5 weeks. The effects of MK-801 (0.0 to 0.1 mg/kg, intraperitoneally) on the electroencephalogram (EEG) and auditory event-related potentials (ERPs) were assessed after 8 weeks of abstinence from EtOH.. Experiments in aim 1 revealed that adolescent EtOH exposure reduced EEG variability in the frontal cortex in the 4 to 6 Hz band but had no effect on cortical and hippocampal EEG power and ERPs. Experiments in aim 2 showed that MK-801 significantly reduced EEG power in the parietal cortex (4 to 6 Hz, 6 to 8 Hz, 8 to 16 Hz, 16 to 32 Hz) and hippocampus (16 to 32 Hz) and EEG variability in the parietal cortex (6 to 8 Hz, 16 to 32 Hz) following adolescent EtOH exposure. MK-801 produced a significant decrease in hippocampal EEG variability (4 to 6 Hz, 8 to 16 Hz, 16 to 32 Hz) in control, but not in EtOH-exposed rats. MK-801 reduced frontal P1 ERP amplitude and latency in response to the rare tone in EtOH-exposed rats compared to controls. In contrast, MK-801 significantly reduced P3 ERP amplitude and latency in control, but not in EtOH-exposed rats.. The effects of MK-801 on hippocampal EEG variability and P3 ERP amplitude and latency are significantly attenuated after a prolonged withdrawal period following adolescent EtOH exposure. However, the inhibitory effects of MK-801 on cortical and hippocampal EEG power were enhanced in rats exposed to EtOH during adolescence. Taken together, these data suggest protracted changes in NMDA systems following adolescent EtOH exposure. Topics: Animals; Body Weight; Central Nervous System Depressants; Cerebral Cortex; Dizocilpine Maleate; Electroencephalography; Ethanol; Evoked Potentials, Auditory; Male; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Time Factors | 2008 |
Lipopolysaccharide does not affect acoustic startle reflex in mice.
Bacterial endotoxin (lipopolysaccharide; LPS) evokes in rodents an adaptive sickness behavior. It also produces changes in stress hormones secretion and activity of brain serotonergic and noradrenergic systems that have been implicated in stress responses, fear, and anxiety. Acoustic startle reflex (ASR) is regarded as a protective behavioral response that is enhanced in threatening situations or following an aversive event, and it can be modulated by physiological and emotional state of an animal. Effects of intraperitoneal injections of LPS on ASR, prepulse inhibition (PPI), locomotor activity in open field, and blood plasma corticosterone concentration were studied in lines of mice that display high (HA line) or low (LA line) swim stress-induced analgesia and also differ in emotional behaviors, including the magnitude of ASR. In both lines LPS produced robust sickness behavior, as evidenced by a decrease in locomotion and body weight, and an increase in corticosterone concentration. However, in neither line LPS injections affected responses to acoustic stimuli as assessed by the ASR and PPI magnitudes. The findings suggest that in sickness behavior induced by LPS the protective responses to salient environmental stimuli are not impaired. The significance of this finding for the concept of sickness behavior is discussed. Topics: Acoustic Stimulation; Analgesia; Animals; Body Weight; Corticosterone; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Injections, Intraperitoneal; Lipopolysaccharides; Male; Mice; Mice, Inbred Strains; Motor Activity; Reflex, Startle; Sick Role; Stress, Physiological; Swimming | 2008 |
Neurodevelopmental impact of antiepileptic drugs and seizures in the immature brain.
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 | 2007 |
Effect of Ocimum sanctum Linn. on cardiac changes in rats subjected to chronic restraint stress.
Male Wistar rats were subjected to chronic restraint stress (CRS; 6 h/day for 21 days) alone or along with either hydroalcoholic extract of Ocimum sanctum (Os; 100 mg/kg; orally) or MK-801, an NMDA receptor antagonist (0.3 mg/kg; i.p.). In the rats subjected to only CRS, plasma cAMP level was significantly raised on day 21, with no significant change in plasma corticosterone level. There was a significant (p < 0.05) fall in myocardial glutathione level, along with a significant (p < 0.05) rise in myocardial superoxide dismutase (SOD) and catalase activities, while light microscopy showed evidence of myocardial edema. Both Os and MK-801 significantly prevented the CRS-induced rise in plasma cAMP level, myocardial SOD and catalase activities as well as the light microscopic changes in the myocardium. This study revealed that Ocimum sanctum protects rat heart from chronic restraint stress induced changes, through its central effect. Topics: Administration, Oral; Animals; Body Weight; Catalase; Corticosterone; Cyclic AMP; Dizocilpine Maleate; Edema; Male; Myocardium; Ocimum; Plant Extracts; Rats; Rats, Wistar; Restraint, Physical; Superoxide Dismutase | 2006 |
Influence of dizocilpine (MK-801) on neurotoxic effect of dexamethasone: behavioral and histological studies.
Elevated levels of endogenous glucocorticoids (GCs) or prolonged treatment with high doses of dexamethasone (DEX) or other GCs preparations are frequently associated with psychosis as well as cognitive deficits, such as the impairment of memory and learning. GCs potentiate stress or ischemia-induced accumulation of excitatory amino acids in the extracellular space of hippocampus. The antagonism of glutamate receptors may potentially improve safety profile of therapy with GCs. The purpose of the present study was to investigate the effect of dizocilpine maleate (MK-801), non-competitive NMDA glutamate receptor antagonist, on neurotoxic effect of the prolonged treatment with the high dose of DEX. The results showed that DEX (120 mg/kg/day for 7 days) impaired the long-term memory and the motor coordination, reduced the body weight and induced the lethality of mice. The morphological and ultrastructural study have confirmed damage to hippocampal neurons especially in the CA3 region after the prolonged treatment with DEX alone. Damaged pyramidal neurons showed robust changes in the shape of the nucleus and cytoplasm condensation. MK-801 alone (at non-toxic dose of 0.3 mg/kg/day), changed neither the behavior of mice nor morphology of the hippocampal neurons. However, it did not prevent the neurotoxic effects of DEX. On the contrary, it intensified DEX-induced neurotoxicity. Topics: Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Body Weight; Dexamethasone; Dizocilpine Maleate; Drug Administration Schedule; Drug Interactions; Excitatory Amino Acid Antagonists; Hippocampus; Male; Microscopy, Electron, Transmission; Neurotoxins; Rats; Retention, Psychology; Statistics, Nonparametric | 2006 |
Early maternal deprivation retards neurodevelopment in Wistar rats.
A single 24 h period of maternal deprivation (MD) in rats has been shown to induce, in adulthood, a number of abnormalities in brain and behaviour that also occur in patients with schizophrenia. However, the short-term behavioural effects of MD have not been studied in detail. Since patients with schizophrenia are characterized by a retardation of normal development, we aimed in the present study to investigate the development of control rats and rats that were exposed to MD on postnatal day 9. Compared to control animals, MD rats showed (1) a reduction in body weight, (2) an increased in reversal latency in negative geotaxis, (3) a delayed eye opening, (4) a delayed emergence of walking and rearing; and (5) a delayed emergence of the behavioural response to amphetamine (amph). On the other hand, MD and control rats responded similarly to the non-competitive NMDA antagonist MK801. These data clearly show that early MD delays development, especially of the dopaminergic system and confirm our hypothesis that MD may represent an interesting animal model for the neurodevelopmental hypothesis of schizophrenia. Topics: Amphetamine; Animals; Animals, Newborn; Body Weight; Dizocilpine Maleate; Eye Abnormalities; Female; Male; Maternal Deprivation; Motor Activity; Nervous System; Neural Inhibition; Rats; Rats, Wistar | 2005 |
Perinatal MK-801 treatment affects age-related changes in locomotor activity from childhood to later adulthood in rats.
Neuronal degeneration underlying the pathology of schizophrenia is already present during childhood. However, most of these studies were done in adult humans or animals. The present study therefore investigated age-related changes of behavior in an innovative version of the Open Field Maze following perinatal chronic administration of the noncompetitive N-methyl-D-aspartate antagonist MK-801. The waxing and waning pattern of locomotor activity during aging with a peak around the age of 90 days was profoundly attenuated by MK-801. MK-801 further reduced locomotion and body weight in mature rats. However, it increased explorative behavior in immature rats. Therefore, the chronic perinatal administration of MK-801 seems to be a model to investigate the pathological mechanisms of psychomotor retardation and body weight dysregulation in schizophrenia. Topics: Age Factors; Aging; Animals; Animals, Newborn; Behavior, Animal; Body Weight; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Exploratory Behavior; Female; Male; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Rats | 2004 |
Early adoption modifies the effects of prenatal stress on dopamine and glutamate receptors in adult rat brain.
Stressful stimuli during pregnancy induce complex effects that influence the development of offspring. These effects can be prevented by environmental manipulations during the early postnatal period. Repeated restraint during the last week of pregnancy was used as a model of prenatal stress, and adoption at birth was used to change the postnatal environment. No differences were found in various physical landmarks, except for testis descent, for which all prenatally stressed pups showed a 1-day delay in comparison with control rats, regardless of the postnatal adoption procedure. Levels of dopamine (DA) D(2) and glutamate (Glu) N-methyl-D-aspartate (NMDA) receptors were differentially regulated in different forebrain regions of cross-fostered adult offspring. Increased concentrations of cortical D(2) receptors detected in stressed pups, raised by a gestationally stressed biological mother, were not detected when the pups were raised by a control mother. Control pups raised by a foster mother whether gestationally stressed or not had higher levels of NMDA receptors in cortical areas. These findings suggest that the normal expression of DA and Glu receptors is influenced by in utero experience and by lactation. The complex pattern of receptor changes reflects the high vulnerability of DA and Glu systems to variations both in prenatal and in postnatal environment, particularly for cortical D(2) receptors and NMDA receptors in cerebral cortex and nucleus accumbens. In contrast, testis descent appears to be more susceptible to prenatal than to postnatal environmental events. Topics: Adoption; Animals; Animals, Newborn; Autoradiography; Behavior, Animal; Benzamides; Body Weight; Brain; Dizocilpine Maleate; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Female; Male; Pregnancy; Prenatal Exposure Delayed Effects; Protein Binding; Rats; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Stress, Physiological; Tritium | 2004 |
Evidence that androgen acts through NMDA receptors to affect motoneurons in the rat spinal nucleus of the bulbocavernosus.
In adult male rats, spinal nucleus of the bulbocavernosus (SNB) motoneurons shrink after castration and are restored in size after androgen treatment. Sixty-day-old Sprague Dawley males were castrated and implanted with SILASTIC capsules containing testosterone (T) or nothing, and osmotic minipumps continuously infusing MK-801, a noncompetitive NMDA receptor antagonist, or saline. Twenty-five days later, bulbocavernosus muscles were injected with the retrograde tracer cholera toxin-horseradish peroxidase conjugate (CT-HRP) to label SNB cells. As seen previously, among saline-treated rats, SNB somata of T-treated castrates were significantly larger than those of castrates receiving blank capsules (p < 0.0001). MK-801 treatment blocked this effect of T on the SNB. MK-801 had no effect on non-androgen-responsive spinal motoneurons in the neighboring retrodorsolateral nucleus (RDLN), nor did the drug affect SNB soma size in the absence of androgen treatment. Motoneuronal soma size in Nissl stain revealed the same pattern of results seen with CT-HRP fills. In situ hybridization indicated that SNB motoneurons express mRNA for the NMDA receptor subunits R1, R2a, and R2b. Castration reduced the expression of R1 mRNA in SNB motoneurons, an effect that was blocked by androgen replacement in castrates. R2A and R2B mRNA expression in SNB cells was not affected by androgen manipulations. Likewise, androgen manipulations had no effect on the expression of any NMDA receptor subtypes in RDLN motoneurons. These results suggest that androgen affects the size of SNB motoneurons by influencing their expression of the NMDA receptor, and therefore the response of the motoneurons to endogenous glutamate. Topics: Animals; Body Weight; Castration; Cell Size; Dizocilpine Maleate; Drug Implants; Excitatory Amino Acid Antagonists; Hormone Replacement Therapy; In Situ Hybridization; Infusion Pumps, Implantable; Lumbosacral Region; Male; Motor Neurons; Neuronal Plasticity; Organ Size; Protein Subunits; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Seminal Vesicles; Spinal Cord; Testosterone | 2002 |
Neuroprotective effects of MK-801 on L-2-chloropropionic acid-induced neurotoxicity.
L-2-Chloropropionic acid is selectively toxic to the cerebellum in rats; the granule cell necrosis observed within 48 h can be prevented by prior administration of MK-801. Short-term treatment (2 h) with L-2-chloropropionic acid has also been shown to activate the mitochondrial pyruvate dehydrogenase complex in fasted adult rats. This study aimed to investigate the effect of prior exposure to MK-801 on the biochemical and neurotoxicological effects of L-2-chloropropionic acid. Extracts were prepared from the forebrain and cerebellum of animals that had been treated with L-2-chloropropionic acid, with and without prior treatment with MK-801, and were analysed using magnetic resonance spectroscopy and amino acid analysis. Glucose metabolism was studied by monitoring the metabolism of [1-(13)C]-glucose using GC/MS. L-2-Chloropropionic acid caused increased glucose metabolism in both brain regions 6 h after administration, confirming activation of the pyruvate dehydrogenase complex, which was not prevented by MK-801. After 48 h an increase in lactate and a decrease in N-acetylaspartate was observed only in the cerebellum, whereas phosphocreatine and ATP decreased in both tissues. MK-801 prevented the changes in lactate and N:-acetylaspartate, but not those on the energy state. These studies suggest that L-2-chloropropionic acid-induced neurotoxicity is only partly mediated by the NMDA subtype of glutamate receptor. Topics: Amino Acids; Animals; Aspartic Acid; Behavior, Animal; Body Weight; Carbon Isotopes; Cerebellum; Creatine; Dizocilpine Maleate; Drug Administration Schedule; Energy Metabolism; Gas Chromatography-Mass Spectrometry; Glucose; Hand Strength; Hydrocarbons, Chlorinated; Lactic Acid; Magnetic Resonance Spectroscopy; Male; Neuroprotective Agents; Propionates; Prosencephalon; Rats | 2001 |
Inhibition of morphine withdrawal by the NMDA receptor antagonist MK-801 in rat is age-dependent.
This study investigated the effects of the NMDA receptor antagonist MK-801 on the development of morphine dependence in 7-, 14-, and 21-day-old rat pups. For 6.5 days, starting at 1, 8, or 15 days of age, rats were pretreated with MK-801 (0.03 or 0.1 mg/kg, bid) or saline; 15 min later, morphine sulfate (10 mg/kg) or saline was injected to induce opiate dependence. On the afternoon of the seventh day, pups were injected with MK-801 (0.1 mg/kg) or saline and 15 min later with naltrexone (1 mg/kg) to precipitate withdrawal. Pups were then placed in a warm chamber with the litter and their behavior scan-sampled every 15 sec for a total of 15 min. MK-801 failed to inhibit morphine withdrawal in the 7-day-old rat, but did attenuate the development of morphine dependence in both the 14- and 21-day-old rats. These results suggest that the NMDA receptor is not functionally active in opiate withdrawal until around the second to third week of postnatal life in the rat and that there exists a transition period for the NMDA receptor to play a role in the development of opiate dependence and withdrawal. Topics: Age Factors; Animals; Body Temperature; Body Weight; Central Nervous System; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Routes; Excitatory Amino Acid Antagonists; Male; Morphine; Morphine Dependence; Naltrexone; Narcotic Antagonists; Narcotics; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome | 2001 |
Chronic prenatal ethanol exposure increases GABA(A) receptor subunit protein expression in the adult guinea pig cerebral cortex.
Excessive consumption of ethanol during pregnancy can produce teratogenic effects in offspring and is the leading cause of mental deficiency in the Western world. The objective of this study was to examine the effects of chronic prenatal ethanol exposure on the number of GABA(A) receptors and relative protein levels for GABA(A) receptor alpha1 and beta2/3 subunits in the adult guinea pig cerebral cortex. Timed pregnant Dunkin-Hartley strain guinea pigs were given one of the following oral treatments daily throughout gestation: 4 gm of ethanol per kilogram of maternal body weight, isocaloric-sucrose with pair feeding, or isovolumetric water with ad libitum access to food. The ethanol treatment resulted in a peak maternal blood ethanol concentration of 328 +/- 55 mg/dl (71.3 +/- 12.0 mm) on gestational day 57 (term, approximately 68 d). Chronic prenatal exposure to ethanol resulted in increased spontaneous locomotor activity throughout development and decreased cerebral cortical weight in adult offspring. The number of cerebral cortical [(3)H]muscimol binding sites was increased in adult offspring from the ethanol treatment group, and there was a corresponding increase in the amount of GABA(A) receptor alpha1 and beta2/3 subunit proteins in these same animals. For individual offspring, there were correlations between locomotor activity and cerebral cortical weight, as well as between cerebral cortical weight and GABA(A) receptor neurochemistry. There was no effect of chronic prenatal ethanol exposure on [(3)H]MK-801 binding in this tissue. These data demonstrate that chronic prenatal ethanol exposure has long-term consequences on the regulation of GABA(A) receptor expression in the cerebral cortex. Topics: Administration, Oral; Animals; Body Weight; Cerebral Cortex; Dizocilpine Maleate; Drug Administration Schedule; Eating; Ethanol; Excitatory Amino Acid Antagonists; Female; GABA Agonists; Guinea Pigs; Male; Motor Activity; Muscimol; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Protein Subunits; Radioligand Assay; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Time | 2001 |
Effect of tributyltin on the N-methyl-D-aspartate (NMDA) receptors in the mouse brain.
The purpose of this study was to determine the effect of tributyltin chloride (TBTCI) on the NMDA receptor by in vitro and in vivo experiments. In the first in vitro experiment, the binding of [3H]MK-801 and of [3H]-CGP39653 were studied in membrane preparations from the cerebral cortex of intact mice to obtain control values. Saturation experiments for [3H]MK-801 and [3H]CGP39653 revealed single binding sites with Kd values of 10.27 and 37.8 nM, and receptor densities of 1.75 and 2.20 pmol/mg of protein, respectively. In the second in vitro experiment, displacement studies were carried out with TBTCI over a concentration range of 0.1 microM to 2 mM. TBTCI inhibited [3H]MK-801 binding but did not affect [3H]CGP39653 binding. In the in vivo experiments, the mice received 1-125 ppm TBTCI in the diet ad libitum for 30 days. Ligand binding to cortical membrane preparations from each mouse was measured by a one-concentration point (2 nM) binding assay. [3H]MK-801 binding was significantly lowered (P < 0.05) in the 5 and 125 ppm TBTCl-exposed animals compared with the controls. [3H]CGP39653 binding was also significantly lowered (P<0.05) in the 1 and 125 ppm TBTCI-exposed animals compared with the controls. These results suggest that the NMDA receptors in the mouse brain are sensitive to relatively low level exposure to TBTCl. Topics: 2-Amino-5-phosphonovalerate; Administration, Oral; Animals; Body Weight; Cell Membrane; Cerebral Cortex; Dizocilpine Maleate; In Vitro Techniques; Male; Mice; Mice, Inbred BALB C; Protein Binding; Receptors, N-Methyl-D-Aspartate; Trialkyltin Compounds | 2001 |
Combined therapy affects outcomes differentially after mild traumatic brain injury and secondary forebrain ischemia in rats.
Muscarinic and NMDA receptors contribute to post-traumatic hypersensitivity to secondary ischemia. However, the effect of these receptor antagonists on behavior and CA1 neuronal death after traumatic brain injury (TBI) with acute (1 h after TBI) forebrain ischemia has not been systematically assessed. We examined cognitive and motor dysfunction and the relationship of behavior deficits to neuronal death in this model using muscarinic and NMDA antagonists. Three behavioral groups (n=10/group) of Wistar rats were subjected to mild TBI and 6 min of forebrain ischemia imposed 1 h after TBI with 45 days survival. Motor and spatial memory performance were assessed using the rotarod task and Morris water maze. Seven additional groups (n=6/group) were evaluated only for CA1 death after 7 days survival following sham, individual or combined injury with and without drug treatments. Rats were given 0.3 mg/kg MK-801 (M) and 1.0 mg/kg scopolamine (S) alone or combined (M-S) before or 45 min after TBI. Rotarod performance was tested at days 1-5 and maze performance on days 11-15 and 40-44 after M-S treatment. The 7-day studies showed M-S treatment (p<0.01) reduced CA1 neuronal death better than either S or M alone. Behavioral groups had inadvertent post-ischemic hypothermia that decreased CA1 death and likely influenced behavioral morbidity. M-S given before TBI (p<0.01) decreased memory deficits on day 15, while M-S treatment given after TBI was ineffective. Unexpectedly, M-S treatment before or after TBI produced transient motor deficits (p<0. 01). Memory improvement occurred independent of CA1 death. Topics: Animals; Body Weight; Brain Injuries; Combined Modality Therapy; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Ischemic Attack, Transient; Male; Maze Learning; Muscarinic Antagonists; Psychomotor Performance; Rats; Rats, Wistar; Scopolamine; Treatment Outcome | 1999 |
Effect of NMDA antagonists on the activity of glutaminase and aspartate aminotransferase in the developing rat cerebellum.
Chronic treatment of rats from postnatal day 6 to 25 with drugs that interact with the N-methyl-D-aspartate (NMDA) receptor induced a differential effect on the activity of some enzymes involved in neurotransmitter synthesis. Two of these drugs ((5R,10S)-(+)-5-methyl-10,11 -dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate (MK-801) and 3-(2-carboxypiperazin-4-yl)propyl-1phosphonic acid (CPP)) caused a marked reduction (20-40%) of glutaminase and aspartate aminotransferase activity in the cerebellum. These changes were observed only at a very precise time of development (i.e. 10 to 19 postnatal day). The competitive antagonist, amino phosphonovaleric acid (APV), did not affect any of the enzymes studied at all tested ages. When animals were treated with NMDA only a slight, but significant, increase in the activity of glutaminase was observed at 9-11 postnatal day only. Any of the agonists or antagonists tested significantly affected the activity of lactate dehydrogenase as compared to control animals. Histologic observations of cerebella treated with the indicated drugs showed that only MK-801, and CPP to a lesser extent, induced a small reduction in the width of the internal granule layer. The body weight of animals treated with MK-801 was clearly reduced, but only in more mature rats (> 16 postnatal day), when animals did not show any alteration in the enzymes tested. These results support the suggestion that presynaptic influences, particularly from glutamatergic neurons, are critical to promote cerebellar granule neurons differentiation during critical periods of the cerebellar development. Topics: 2-Amino-5-phosphonovalerate; Age Factors; Animals; Aspartate Aminotransferases; Body Weight; Cell Differentiation; Cerebellum; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Glutaminase; L-Lactate Dehydrogenase; Male; Nerve Fibers; Nerve Tissue Proteins; Neurons; Organ Specificity; Piperazines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission | 1999 |
Chronic ethanol exposure alters MK-801 binding sites in the cerebral cortex of the near-term fetal guinea pig.
The mechanism of ethanol central nervous system (CNS) teratogenesis, resulting from chronic maternal ingestion of high-dose ethanol during pregnancy, is not clearly understood. One of the target sites for ethanol-induced damage in the developing brain is the cerebral cortex. It has been proposed that chronic prenatal ethanol exposure alters NMDA receptors in the developing cerebral cortex. To test this hypothesis, timed pregnant guinea pigs were administered one of the following oral treatments throughout gestation: 4 g ethanol/kg maternal body weight/day; isocaloric sucrose/pair-feeding; water; or no treatment (ad lib). Near-term fetuses were studied at gestational day (GD) 63 (term, about GD 68). This ethanol regimen produced a maternal blood ethanol concentration of 66+/-4 mM (304+/-19 mg/dl) at 1 h after the daily dose on GD 58. The chronic ethanol regimen decreased near-term fetal body weight (12-26% decrease), brain weight (23% decrease), and cerebral cortical weight (21% decrease), compared with the isocaloric sucrose/pair-feeding, and combined water/ad lib experimental groups. Saturation analysis of near-term fetal cerebral cortical membranes using a [3H]MK-801 radioligand binding assay demonstrated a decreased affinity and increased number of MK-801 binding sites for the chronic ethanol regimen compared with the control treatments. These data support the suggestion that upregulation of NMDA receptors in the cerebral cortex after chronic prenatal ethanol exposure could lead to NMDA receptor-mediated excitotoxicity in this brain region. Topics: Animals; Body Weight; Brain; Cerebral Cortex; Dizocilpine Maleate; Ethanol; Female; Fetal Blood; Fetus; Gestational Age; Guinea Pigs; Maternal-Fetal Exchange; Organ Size; Pregnancy; Receptors, N-Methyl-D-Aspartate | 1999 |
MK-801 potentiates ethanol's effects on locomotor activity in mice.
FAST vs. SLOW selected mouse lines and C57BL/6J (B6) vs. DBA/2J (D2) inbred strains differ in their sensitivities to ethanol's locomotor stimulant effects, and provide two unique sets of genetic animal models to study neurophysiological substrates of this behavior. To determine whether NMDA receptor function mediates sensitivity to ethanol's stimulant effects, we assessed the effects of the noncompetitive NMDA antagonist, MK-801, on locomotor activity of naive and ethanol-treated FAST, SLOW, B6, and D2 mice. MK-801 (0.01-0.5 mg/kg, I.P.) had biphasic effects in all genotypes, with stimulation at moderate doses and decreased activation at the highest dose. FAST mice were more activated by MK-801 than SLOW mice, suggesting that selection differentially altered NMDA receptor function between the lines. B6 and D2 mice did not differ in locomotor responses following MK-801 administration. Stimulant doses of MK-801 decreased or blocked ethanol-stimulated locomotor activity in FAST and D2 mice, and potentiated the locomotor depressant actions of ethanol in SLOW and B6 mice. Potentiation of ethanol's activating properties was observed in one treatment group in D2 mice. These data suggest that NMDA receptors modulate ethanol's stimulant properties, by a more significant involvement in expression of ethanol's locomotor depressant properties. Topics: Aging; Animals; Body Weight; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Synergism; Ethanol; Excitatory Amino Acid Antagonists; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Motor Activity; Receptors, N-Methyl-D-Aspartate | 1998 |
A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats.
This study used streptozotocin (STZ; 50 mg/kg i.p.) diabetic rats and monitored weekly thermal and mechanical nociceptive thresholds for 8 weeks diabetes. Rats developed mechanical hyperalgesia as soon as 2 weeks after STZ injection. Thermal nociceptive threshold was not altered up to 8 weeks after STZ injection. Four week-diabetic rat mechanical hyperalgesia showed reduced sensitivity to the antinociceptive effect of morphine (5-20 mg/kg i.p.). Furthermore, a reduced sensitivity to the antinociceptive effect of the GABA(B) agonist, (+/-)baclofen, was observed. A dose as high as 16 mg/kg i.p. of (+/-)baclofen was necessary to reverse 4 week-diabetic rat hyperalgesia, whereas in control rats the highest antinociceptive dose devoid of muscle-relaxant effect was 4 mg/kg i.p. The non-peptide antagonist for the substance P, neurokinin, (NK1) receptor, RP 67580 (3-9 mg/kg i.p.) was not effective in reversing the mechanical hyperalgesia associated with 4 week-diabetes. A six day-treatment with an antagonist for the N-methyl-D-aspartate (NMDA) receptor for glutamate, (+)MK-801 (0.1 mg/kg i.p. twice a day), gradually but completely reversed 4 week-diabetes-induced mechanical hyperalgesia. These data suggest that diabetes-induced hyperalgesia may be the consequence of increased activity of primary afferent fibres leading to an increased excitatory tone within the spinal cord. An increased release of glutamate and activation of the NMDA receptor, would maintain the hyperalgesic state. Reduced activity of both opioidergic and GABA(B)ergic inhibitory systems, might exacerbate the increased excitation thus contributing to the ongoing pain. It is suggested that NMDA receptor antagonists may constitute an alternative therapy for diabetic neuropathic pain. Topics: Animals; Baclofen; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dizocilpine Maleate; GABA Agonists; GABA-B Receptor Agonists; Hyperalgesia; Indoles; Isoindoles; Male; Neurokinin-1 Receptor Antagonists; Physical Stimulation; Pressure; Rats; Rats, Wistar; Sciatic Nerve; Spinal Cord; Substance P | 1998 |
Immediate and long-term effects of neonatal MK-801 treatment on nonspatial learning.
These experiments observed the immediate and long-term effects of neonatal treatment with MK-801 on patterned single alternation (PSA), a form of nonspatial, memory-based learning. Rat pups were injected daily on postnatal days (PND) 7-19, with MK-801 (MK+) or the less active isomer of MK-801 (MK-) (0.25 mg/kg), and trained at either PND 22 or 60. Rats treated with MK+ or MK- and trained on PND 22 were significantly impaired in PSA when compared with the saline control. Beyond the learning impairment, MK+ rats showed an overall decreased running speed during training. They also presented an array of abnormal behaviors and significant weight loss. These nonassociative variables were determined for several doses (0.025, 0. 05, 0.1, 0.15, and 0.20 mg/kg) through PND days 22-25. Rats that received the threshold dose for secondary effects (0.025 mg/kg) also showed an overall decrease in running speed, but failed to show a significant nonspatial learning impairment on PSA. The PSA learning impairment was found to be not long lasting; rats trained at PND 60, after neonatally receiving the original high dose of MK-801, did not differ from controls. Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Learning; Male; Memory; Rats; Rats, Sprague-Dawley; Running; Stereoisomerism; Vocalization, Animal | 1998 |
Prenatally malnourished female but not male rats show increased sensitivity to MK-801 in a differential reinforcement of low rates task.
A reduced behavioral sensitivity to drugs acting on central GABAergic, serotonergic, opioid and cholinergic systems has previously been identified in predominantly male malnourished animals. The present study sought to compare the effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 on responding maintained by a differential reinforcement of low rates (DRL-18s) operant schedule in two groups of rats with different prenatal nutritional histories (well-nourished and protein restricted). The schedule required that the rats space their responses at least 18 s apart in order to obtain food reinforcement (timing behavior). After training to a stable high proficiency, MK-801 was administered to female rats (Experiment 1) at doses of 0 (saline), 0.004, 0.008, 0.016, 0.024 or 0.032 mg/kg (doses expressed as the free-base). MK-801 produced dose-dependent decreases in the percentage efficiency of responding and the number of rewarded responses, with dose-dependent increases in the number of responses emitted. Prenatal malnutrition significantly shifted the inter-response time (IRT) curve to the left, relative to that of the well-nourished controls, leading to a significantly lower efficiency and a lower number of reinforcers, at an MK-801 dose of 0.016 mg/kg. In Experiment 2, the effect of MK-801 on DRL performance was compared between male and female rats after prenatal malnutrition. In general, females proved more sensitive to MK-801 than males. Consistent with Experiment 1, a significantly greater drug impairment was observed in prenatally malnourished females compared with well-nourished females, albeit at a slightly higher dose (0.032 mg/kg). Prenatal malnutrition did not alter the drug response in male rats. These findings suggest that the behavioral response to NMDA blockade is augmented in adult female, but not male, rats after prenatal malnutrition. Topics: Animals; Body Weight; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Male; Nutrition Disorders; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Sex Characteristics | 1998 |
Effect of prior receptor antagonism on behavioral morbidity produced by combined fluid percussion injury and entorhinal cortical lesion.
We have used an animal model of traumatic brain injury (TBI) that incorporates both the neurotransmitter toxicity of fluid percussion TBI and deafferentation of bilateral entorhinal cortical (BEC) lesion to explore whether administration of muscarinic cholinergic or N-methyl-D-aspartate glutamatergic antagonists prior to injury ameliorates cognitive morbidity. Fifteen minutes prior to moderate central fluid percussion TBI, rats were given intraperitoneal injections of either scopolamine (1.0 mg/kg) or MK-801 (0.3 mg/kg) and 24 hr later underwent BEC lesion. Body weight was followed for 5 days postinjury, as was beam balance and beam walk performance to assure motor recovery prior to spatial memory testing. Each group was assessed for spatial memory deficits with the Morris water maze at short term (days 11-15) and long-term (60-64 days) postinjury intervals and then compared with untreated combined insult and sham-injured controls. Results showed that each drug significantly elevated body weight relative to untreated injured cases. Both scopolamine and MK-801 reduced beam balance deficits, whereas neither drug had a significant effect on beam walk deficits. Interestingly, short-term cognitive deficits assessed on days 11-15 were differentially affected by the two drugs: MK-801 pretreatment enhanced the recovery of spatial memory performance, whereas scopolamine pretreatment did not. Long-term (days 60-64) deficits in spatial memory were not altered by pretreatment with either drug. Our results suggest that, unlike fluid percussion TBI alone, behavioral impairment may require more select intervention when deafferentation is part of the head trauma pathology. Topics: Animals; Body Temperature Regulation; Body Weight; Brain Injuries; Dizocilpine Maleate; Entorhinal Cortex; Excitatory Amino Acid Antagonists; Male; Maze Learning; Muscarinic Antagonists; Neuroprotective Agents; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Scopolamine | 1997 |
Neuroprotection afforded by MK-801 against L-2-chloropropionic acid-induced cerebellar granule cell necrosis in the rat.
Administration of a single oral dose of 750 mg/kg L-2-chloropropionic acid (L-CPA) to rats produces marked necrosis to the granule cell layer of the cerebellum by 48 h after dosing. Associated with the neuropathology the rats show locomotor impairment and a loss of body weight and a significant increase in cerebellar water and sodium content, indicating an oedematous reaction. Cerebellar aspartate and glutamate concentrations were reduced, while glycine and glutamine concentrations were increased after this treatment. Administration of the N-methyl-D-aspartate (NMDA) receptor channel antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,1 0-imine (MK-801), 30 min prior to L-CPA at a dose of 0.5, 1 or 5 mg/kg i.p. prevented the necrosis to the granule cell layer of the cerebellum and the signs of motor incoordination. Similarly there was no loss in cerebellar aspartate or glutamate concentration or increase in water or sodium content. Prior treatment with MK-801 at 0.1 mg/kg did not afford protection against the neurotoxicity. Post-treatment with 1 mg/kg MK-801 up to 1 h after administering L-CPA afforded complete neuroprotection, however if delayed until 2 or 6 h it gave only partial protection, and after 12 h it gave no protection. Administration of MK-801 alone at 5 mg/kg i.p., did not alter water content, sodium concentration, aspartate or glutamate concentrations in the cerebellum. In conclusion, we have shown that MK-801 given prior to and 1 h after L-CPA can afford complete neuroprotection, suggesting that a sub-population of NMDA receptors located on granule cells in cerebellum play a key role in mediating the selective toxicity of this chemical to the rat cerebellum. Topics: Amino Acids; Animals; Body Water; Body Weight; Cerebellum; Dizocilpine Maleate; Hydrocarbons, Chlorinated; Male; Necrosis; Neurotoxins; Propionates; Rats; Sodium | 1997 |
Non-competitive antagonism of N-methyl-D-aspartate receptor inhibits tolerance to the analgesic action of U-50,488H, a kappa-opiate receptor agonist in the rat.
1. The effect of dizocilpine (MK-801), a non-competitive inhibitor of N-methyl-D-aspartate (NMDA) receptor on the development of tolerance to the analgesic and hypothermic actions of U-50,488H, a highly selective kappa-opiate receptor agonist, was determined in the rat. 2. Male Sprague-Dawley rats were made tolerant to the pharmacological actions of U-50,488H by twice daily intraperitoneal (i.p.) injections of the drug (25 mg/kg) for 4 days. 3. Multiple injections of U-50,488H resulted in the development of tolerance to its analgesic and hypothermic actions in the rat. MK-801 injected 10 min before each injection of U-50,488H, dose-dependently inhibited the development of tolerance to the analgesic action but the tolerance to the hypothermic action of U-50,488H was unaffected. 4. Multiple injections of U-50,488H decreased the body weight gain. MK-801 dose-dependently decreased the gain in body weight further. 5. The results indicate that non-competitive antagonism of the NMDA receptor by MK-801 can selectively inhibit the tolerance to the analgesic action of U-50,488H in the rat, however, such an effect was associated with significant decreases in normal gain in body weight. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Body Temperature; Body Weight; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Tolerance; Male; Pain Measurement; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, kappa; Time Factors | 1995 |
In vitro and in vivo effects of lead on specific 3H-MK-801 binding to NMDA-receptors in the brain of mice.
The in vitro and vivo effects of lead on the NMDA-receptors in adult and juvenile mice were studied by means of receptor binding assays. Adult female NMRI-mice received 100 and 1,000 ppm lead as nitrate in their drinking water for 30 and 90 days. Perinatal exposure was achieved by treating gestating mice from the 5th day post conception with 0, 100 or 1,000 ppm lead in their drinking water. Characterization of the NMDA N-methyl-D-aspartate)-receptor was carried out ex vivo using binding studies on homogenates of the forebrain with the non competitive NMDA-antagonist 3H-MK-801. In vitro, complete inhibition of the radioligand binding was found with half maximal inhibiting concentrations (IC50-values) of 19.7 +/- 2.6 microM (SEM) in absence of amino acids and 9.5 +/- 0.9 in presence of glutamate and glycine. These concentrations are in a range which could be achieved in vivo, e.g. the lead content in the forebrain of juvenile mice treated with 1,000 ppm lead was 10.0 +/- 1.8 mumol/kg wet weight. It was speculated that lead binds at the zinc binding site. In the presence of amino acids and divalent cations, such as calcium or magnesium, low lead concentrations lead to a significant increase in receptor affinity. Analysis of the saturation experiments carried out on forebrain homogenates of lead-treated animals showed a slight increase in receptor density of 13 or 15% with an unchanged Kd-value only in the adult animals treated with 100 ppm lead and in absence of stimulating amino acids.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Aging; Animals; Binding, Competitive; Body Weight; Brain; Dizocilpine Maleate; Female; Kinetics; Lead; Mice; Organ Size; Receptors, N-Methyl-D-Aspartate; Zinc | 1995 |
The effect of anosmia on MK-801-induced behaviour in mice.
Systemic administration of N-methyl-D-aspartate (NMDA) receptor antagonists induces a well defined behaviour in rodents characterized by, for example increased locomotion and ataxia. It is not clear in what brain region(s) NMDA antagonists induce this behaviour. We have studied the possible involvement of olfactory pathways by making adult mice anosmic via intranasal injection of zinc sulphate, a procedure that is known to destroy the olfactory epithelium. The NMDA antagonist MK-801 was given intraperitoneally (0.1-1.0 mg/kg) and the animals were scored for locomotion and ataxia 60-90 min later. Before MK-801 administration, olfactory-lesioned mice did not differ from non-lesioned controls with regard to locomotion or ataxia. MK-801 caused locomotor activation (> or = 0.2 mg/kg) and ataxia (> or = 0.5 mg/kg) in both groups. In general, olfactory-lesioned animals showed more locomotion and less ataxia after MK-801 administration than non-lesioned animals. Lesioned animals displayed 2.0- (P < 0.05) and 3.7-fold (P < 0.05) more extensive locomotor activation than non-lesioned animals after 0.5 and 1.0 mg/kg of MK-801, respectively. No difference in the degree of ataxia was seen between the two groups at 0.5 mg/kg, whereas non-lesioned animals showed a 2.1-fold higher degree of ataxia after 1.0 mg/kg of MK-801, indicating that the enhanced MK-801-induced locomotor activation in olfactory-lesioned mice was not simply due to less ataxia. These results suggest that olfactory input is involved in NMDA antagonist-induced behaviour. Topics: Animals; Ataxia; Behavior, Animal; Body Weight; Denervation; Dizocilpine Maleate; Excitatory Amino Acids; Male; Mice; Motor Activity; Nerve Degeneration; Neurons, Afferent; Olfaction Disorders; Olfactory Bulb; Organ Size; Sulfates; Zinc Compounds; Zinc Sulfate | 1995 |
Cardiac hypertrophy secondary to status epilepticus in the rat.
Status epilepticus was induced in rats by sequential injections of lithium and pilocarpine. Seizure activity was aborted by a combination of MK-801 and diazepam, with status duration ranging from 3 to 180 min. When the hearts were examined 8-12 days later, rats that had experienced an episode of status epilepticus had significantly heavier hearts than did controls. The nature of the cardiac tissue changes was not examined, and deserves further study. Topics: Animals; Body Weight; Cardiomegaly; Diazepam; Dizocilpine Maleate; Electroencephalography; Lithium Chloride; Male; Myocardium; Organ Size; Pilocarpine; Rats; Rats, Sprague-Dawley; Status Epilepticus | 1995 |
Effects of acute and chronic administration of dizocilpine on the pharmacological responses to U-50,488H and brain and spinal cord kappa-opioid receptors in the rat.
In male Sprague-Dawley rats, acute and chronic effects of dizocilpine (MK-801), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, were determined on the analgesic and hypothermic actions of U-50,488H, a kappa-opioid receptor agonist. In addition, the in vitro effects of MK-801 on the binding of [3H]ethylketocyclazocine ([3H]EKC) to kappa-opioid receptors in brain and spinal cord of the rat were determined. A single injection of MK-801 given 10 min prior to U-50,488H or given twice a day for 4 days dose-dependently enhanced the analgesic action of U-50,488H. The enhancement of the analgesic response was much greater in rats injected chronically with MK-801 as compared with those injected acutely. Both single and multiple injections of MK-801 failed to affect the hypothermic action of U-50,488H. In vitro, MK-801 inhibited the binding of [3H]EKC to brain and spinal cord membranes with IC50 values of 9.80 +/- 1.7 and 1.37 +/- 0.58 microM, respectively. Chronic administration of MK-801 twice a day for 4 days increased the Bmax value of [3H]EKC binding in the brain, but had no effect on Kd. On the other hand, chronic treatment with MK-801 decreased the Kd of [3H]EKC binding in spinal cord without affecting Bmax. It is concluded that blockade of NMDA receptor enhances the analgesic response to a kappa-opioid receptor agonist and upregulates brain and spinal cord kappa-opioid receptors. Finally, the results suggest that the NMDA receptor may have a role in the regulation of kappa-opioid systems. Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Opioid; Animals; Body Temperature; Body Weight; Brain Chemistry; Dizocilpine Maleate; Ethylketocyclazocine; Excitatory Amino Acid Antagonists; In Vitro Techniques; Kinetics; Male; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Spinal Cord | 1995 |
Neonatal testosterone exposure influences neurochemistry of non-opioid swim stress-induced analgesia in adult mice.
The effects of neonatal hormone manipulations on swim stress-induced analgesia (SSIA) magnitude and neurochemical quality were examined in Swiss-Webster mice of both sexes. Previous research has indicated that non-opioid SSIA mechanisms in adult Swiss-Webster mice are sexually dimorphic. Male mice exhibit non-opioid SSIA following a 3-min swim in cold (15 degrees C) water that is antagonized by the non-competitive NMDA antagonist MK-801 (dizocilpine; 0.075 mg/kg), whereas female mice do not display NMDA-mediated analgesia in the presence of estrogen. Since male and female mice show equipotent magnitudes of SSIA, it was concluded that female mice display a neurochemically distinct, estrogen-dependent SSIA mechanism specific to their gender. In the present study, female mice exposed to testosterone during the neonatal period display NMDA-mediated analgesia even in the presence of estrogen in adulthood. Thus, expression of the female-specific, estrogen-dependent SSIA mechanism previously described may be dependent on the absence of testosterone during early ontogeny. Topics: Analgesia; Animals; Animals, Newborn; Body Weight; Brain; Dizocilpine Maleate; Estrogens; Excitatory Amino Acid Antagonists; Female; Male; Mice; Orchiectomy; Pain Measurement; Pregnancy; Receptors, N-Methyl-D-Aspartate; Sex Characteristics; Stress, Psychological; Swimming; Testosterone | 1995 |
Tolerance to and dependence on MK-801 (dizocilpine) in rats.
Rats were trained to respond under a fixed-ratio 30 schedule for food presentation during four daily 0.5-h sessions occurring every 6 h. After stable baseline response was established, osmotic minipumps were implanted that infused vehicle or (+)-5 methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine hydrogen maleate (dizocilpine; MK-801), SC. Behavioral sessions continued to be conducted daily. After 10 days the infusion pumps were removed. Vehicle and 0.10 mg/kg per day MK-801 did not affect behavior during infusions or after cessation of dosing. Dosing with 0.32 and 0.56 mg/kg per day initially suppressed responding, but tolerance developed to these effects. After the infusions were stopped, a dose-dependent disruption of operant behavior occurred. Response rates for the 0.32 and 0.56 mg/kg per day infusion groups were suppressed to 41 and 27% of preinfusion control response rates, respectively, the day after dosing stopped; however, no physical signs of abstinence were observed. Response rates recovered toward control over the next 2-4 days. In a separate experiment, the suppression of response produced by abstinence from 0.32 mg/kg per day of MK-801 (SC) for 10.5 days was reversed by readministration of MK-801 (IP). These results demonstrate that MK-801 produces dependence, as evidenced by the emergence of a behavioral abstinence syndrome after cessation of dosing. Topics: Animals; Body Weight; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Tolerance; Infusion Pumps, Implantable; Male; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Substance-Related Disorders | 1994 |
In vivo assessment of prevention of white-noise-induced seizure in magnesium-deficient rats by N-methyl-D-aspartate receptor blockers.
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 | 1994 |
Effects of chronic treatment with (+)- and (-)-nicotine on nicotinic acetylcholine receptors and N-methyl-D-aspartate receptors in rat brain.
In this study, the effects of chronic treatment with (+)-nicotine on brain nicotinic acetylcholine receptors (nAChRs) and N-methyl-D-aspartate (NMDA) receptors, as well as on animal body weight were compared with those of chronic treatment with (-)-nicotine. Male Sprague-Dawley rats were s.c. injected with saline, (+)-nicotine (2.0 mg free base/kg b.w.) or (-)-nicotine (0.45 mg free base/kg b.w.) for 18 days. Brain nAChRs were investigated by (-)-[3H]nicotine binding. A significant increase in the high-affinity (-)-[3H]nicotine (5 nM)-binding sites was observed in the cortex, hippocampus, midbrain and striatum but not in the cerebellum of the rats treated with either (+)- or (-)-nicotine. The displacement curves of (-)-[3H]nicotine/(-)-nicotine in the cortices of rats treated with either (+)- or (-)-nicotine showed only one population of high-affinity binding sites, whereas both high- and low-affinity binding sites were observed in the cortices of control animals. Brain NMDA receptors were studied by [3H]MK-801, which binds to the NMDA receptor-ion channel complex. A significant decrease in the Bmax, but not in the KD for [3H]MK-801 binding in the cortices of rats treated with either (+)- or (-)-nicotine was only detected under certain experimental conditions where the NMDA receptors seem not to be maximally activated. The body weight of the animals treated with (-)-nicotine was significantly lower than that of the control animals, whereas there was no difference in body weight between (+)-nicotine- and saline-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Amino Acids; Animals; Body Weight; Brain; Dizocilpine Maleate; Male; Nicotine; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Stereoisomerism; Time Factors | 1994 |
Structural, neurochemical and behavioural consequences of neonatal blockade of NMDA receptor through chronic treatment with CGP 39551 or MK-801.
Recent evidence suggests that NMDA receptors may be involved in survival of neurons and establishment of correct connectivity during development. We have treated rat pups from postnatal day 1 to 22 with daily s.c. injections of a competitive (CGP 39551) and a non-competitive (MK-801) antagonist of the NMDA receptor. Body weight of treated rats was decreased by 50-65% at postnatal day 24 and by 25-32% at 70 days of age. Brain weight was decreased by 16-24% at both ages. Among the different brain regions, the cerebellum and striatum appeared more decreased in size than the cortex and hippocampus. Only few minor, and in some cases transient, differences were measured in the cerebellum, the hippocampus and the cortex for a battery of neurochemical markers related to cholinergic, GABAergic and glutamatergic transmission as well as to astrocyte and oligodendrocyte activity. When tested in actometric cages from postnatal days 28 to 60, treated rats exhibited a dramatic increase of spontaneous locomotor activity which was maximal in 28-day-old animals (380% and 250% of control values in CGP 39551 and MK-801 groups, respectively) and was still significant at 60 days of age. Therefore, long-lasting alteration of motor behaviour is obtained by the schedule of chronic treatment adopted for the present experiments. Our results suggest that blockade of NMDA receptors during the critical period of brain maturation may result in permanent alteration of neural circuits. Topics: 2-Amino-5-phosphonovalerate; Animals; Animals, Newborn; Behavior, Animal; Body Weight; Brain; Brain Chemistry; Choline O-Acetyltransferase; Dizocilpine Maleate; Female; Motor Activity; Pregnancy; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate | 1993 |
Dizocilpine (MK-801) blocks tolerance to the analgesic but not to the hyperthermic effect of morphine in the rat.
The effect of dizocilpine (MK-801), an N-methyl-D-aspartate receptor antagonist, on the development of tolerance to the analgesic and hyperthermic effects of morphine was determined in the rat. Tolerance to morphine in male Sprague-Dawley rats was induced by implanting subcutaneously 6 morphine pellets during a 7-day period. Two schedules of intraperitoneal injections of MK-801 were used. In one, the drug was injected once a day, and in the other it was injected twice a day. The doses of MK-801 were 0.03, 0.1 and 0.3 mg/kg. In the treatment once a day, MK-801 blocked the development of tolerance to the analgesic effect of morphine, but there was no dose-dependent effect. In the treatment twice a day, MK-801 produced a dose-dependent inhibition of tolerance to the analgesic effect of morphine. Higher doses of MK-801 produced high mortality. MK-801 given once a day or twice a day failed to affect the tolerance to the hyperthermic effect of morphine. In both schedules of MK-801 treatment, the highest dose of MK-801 resulted in high mortality. It is concluded that MK-801 is selective in blocking the tolerance to the analgesic effect of morphine in the rat. Topics: Analgesia; Animals; Body Weight; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Tolerance; Fever; Male; Morphine; Rats; Rats, Sprague-Dawley | 1993 |
Sex differences in the antagonism of swim stress-induced analgesia: effects of gonadectomy and estrogen replacement.
Sex differences in the neurochemical mediation of swim stress-induced analgesia (SSIA) were examined in Swiss-Webster mice. Intact and gonadectomized adult mice of both sexes were tested for their analgesic response (hot-plate test) to 3 min of forced swimming in 15 degrees C and 20 degrees C water. SSIA resulting from 15 degrees C swim was previously shown to be naloxone-insensitive (i.e., non-opioid) whereas SSIA resulting from 20 degrees C swim produced an analgesia that was partially reversible by naloxone (i.e., mixed opioid/non-opioid). The non-opioid components of these SSIA paradigms were attenuated by the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801). We now report that in males, but not females, dizocilpine (0.075 mg/kg, i.p.) and naloxone (10 mg/kg, i.p.) antagonized the non-opioid and opioid components of SSIA, respectively. After ovariectomy, females displayed a pattern of antagonism similar to males such that dizocilpine attenuated non-opioid SSIA, although naloxone remained ineffective in antagonizing 20 degrees C SSIA. Thus, SSIA in intact females was neither opioid- nor NMDA-mediated, yet it was of similar magnitude to the SSIA displayed by intact males. In separate experiments, estrogen replacement (estrogen benzoate; 5.0 micrograms/day, i.p.) administered to ovariectomized mice over a 6-8 day period reinstated the dizocilpine-insensitivity of 15 degrees C SSIA characteristic of intact females. However, a similar estrogen regimen administered to both intact and castrated males did not compromise the sensitivity to dizocilpine previously noted in male mice.(ABSTRACT TRUNCATED AT 250 WORDS) Topics: Analgesia; Animals; Body Weight; Dizocilpine Maleate; Estrogens; Female; Male; Mice; Naloxone; Orchiectomy; Ovariectomy; Pain Measurement; Reaction Time; Sex Characteristics; Stress, Psychological; Swimming | 1993 |
Subchronic MK-801 treatment to juvenile rats attenuates environmental effects on adult spatial learning.
Treatment with the non-competitive NMDA receptor blocker MK-801 (0.16 mg/kg), given to juvenile rats before and after the exposure to an enriched environment on alternate days for 4 weeks, attenuated the improvements in spatial learning and open field adaptation which resulted from such environmental stimulation. Drug treatment affected the consolidation of experiences as an injection given after exposure to the enriched environment was needed to demonstrate this effect. In addition, MK-801 administration diminished the adverse effect of stimulus deprivation-the slow learning rate normally seen in rats housed in impoverished environment. Radioligand binding studies showed that drug treatment decreased [3H]MK-801 binding sites in cortex. The learning, activity and receptor binding effects were measured 4 months from cessation of the drug treatment and environmental manipulation. The results support the role of NMDA receptors in mediating cognitive changes associated with environmental stimulation. Topics: Animals; Body Weight; Cerebral Cortex; Dizocilpine Maleate; Environment; Exploratory Behavior; Hippocampus; Learning; Male; Motor Activity; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Space Perception; Synaptic Membranes | 1993 |
Chronic neonatal NMDA receptor blockade with MK-801 alters monoamine metabolism in the adult rat.
Administration of non-competitive N-methyl-D-aspartate (NMDA) antagonists in rodents leads to a characteristic motor syndrome which has been related to changes in monoamine metabolism in a variety of brain regions. We examined the question whether chronic MK-801 treatment in neonatal rats from postnatal day 8 through 19, which has been shown previously to alter NMDA receptor function, would also affect monoamine metabolism in striatum and frontal cortex of adult rats. Monoamines and their metabolites were determined 5 months after the treatment using high-performance liquid chromatography with electrochemical detection. Dihydroxyphenylacetic acid (DOPAC) concentration was elevated (greater than 40%) in both regions tested, while 5-hydroxyindoleacetic acid (5-HIAA) concentration was significantly elevated only in the cortex (19%), and 3-methoxy-4-hydroxyphenylglycol (MHPG) only in the striatum (47%). These results demonstrate that the long-lasting effects of chronic neonatal MK-801 treatment are not restricted to glutamate transmission, but include monoamine transmission as well. Topics: Age Factors; Animals; Animals, Newborn; Ataxia; Biogenic Amines; Body Weight; Corpus Striatum; Dizocilpine Maleate; Dopamine; Frontal Lobe; Growth Disorders; Male; Motor Activity; Norepinephrine; Nutrition Disorders; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Serotonin; Synaptic Transmission | 1992 |
Sensitization to the toxic effects of cocaine in mice is associated with the regulation of N-methyl-D-aspartate receptors in the cortex.
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 | 1992 |
Serial injections of MK 801 (Dizocilpine) in neonatal rats reduce behavioral deficits associated with X-ray-induced hippocampal granule cell hypoplasia.
MK 801 (NMDA antagonist) has been shown to protect newborns from hypoxia-induced brain damage. Here, we determined if (+)-5-methyl-10,11-dihydroxy-5h-dibenzo (a,d)cyclohepten-5,10-imine (MK 801) could attenuate behavioral deficits associated with early radiation-induced hypoplasia of fascia dentata granule cells. We pretreated neonatal rats (n = 20) with MK 801 (0, 0.1, or 0.2 mg/kg, IP) before each of eight fractionated, head-only doses of X-rays (13 Gy total) administered during the first 16 days postpartum. Other rats (n = 18) received the same drug treatments but were sham irradiated. At age 16 months, water-escape latencies to a submerged platform were measured in a water maze. Irradiated rats with hippocampal damage exhibited impaired learning (longer latencies to find the platform) than did sham-irradiated subjects. Moderate doses of MK 801 (0.1 mg/kg) facilitated the learning of the water maze by irradiated subjects but did not enhance the number of their fascia dentata granule cells. Higher doses (0.2 mg/kg) of MK 801 provided no behavioral benefits. In fact, this dose significantly impaired the learning of the water maze by sham-irradiated rats and potentiated the granule cell hypoplasia observed in irradiated subjects. Thus, early MK 801 treatment produces dose-dependent behavioral protection for rats with radiation-induced hippocampal damage. Future studies may reveal the neurophysiological and neuroanatomic substrates of this behavioral recovery. Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Dizocilpine Maleate; Female; Hippocampus; Pregnancy; Radiation Injuries, Experimental; Rats; X-Rays | 1992 |
Antagonism of the toxicity of cocaine by MK-801: differential effects in spontaneously hypertensive and Wistar-Kyoto rats.
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 | 1992 |
Effects of chronic administration of MK-801 upon local cerebral glucose utilisation and ligand binding to the NMDA receptor complex.
Although clinical use of N-methyl-D-aspartate (NMDA) receptor antagonists will involve prolonged drug administration, knowledge of the functional consequences of chronic NMDA receptor blockade is limited. Local cerebral glucose utilisation was measured in conscious rats in 74 discrete brain regions after chronic administration of (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine (MK-801) (0.5 mg/kg i.p.). Chronic treatment with MK-801 caused small, significant changes in glucose use in 4 of the 74 brain areas; parietal cortex (-13%), frontal cortex (-10%), subthalamic nucleus (-14%) and nucleus accumbens (-17%). These focal alterations in glucose use were not associated with changes in ligand binding to various sites within the NMDA receptor complex (i.e. agonist recognition site, glycine site, ion channel site) which were assessed autoradiographically. The acute effects of MK-801 on glucose utilisation were significantly enhanced after chronic MK-801 in 7 brain regions (e.g. frontal and parietal cortices) and attenuated in 6 brain regions (e.g. nucleus accumbens, hippocampus, posterior cingulate cortex). Neither local enhancement nor attenuation of the acute response to MK-801 was due to alterations in ligand binding to sites within the NMDA receptor complex. The data clearly indicate that the functional consequences of NMDA blockade are altered after chronic MK-801 treatment in an anatomically organised, though complex manner. These adaptive functional changes after chronic MK-801 treatment cannot be attributed readily to alterations in the NMDA receptor complex in affected regions. Topics: Animals; Autoradiography; Behavior, Animal; Body Weight; Brain; Brain Chemistry; Dizocilpine Maleate; Glucose; Hemodynamics; Ligands; Male; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Respiration | 1991 |
Neuronal and glial marker proteins in the evaluation of the protective action of MK 801.
A quantitative dot immunobinding procedure was used to quantify glial [the S-100 protein and the glial fibrillary acidic (GFA) protein] and neuronal (the 68- and 200-kDa neurofilament polypeptides, neuron-specific enolase, and neuronal cell adhesion molecule) markers. A single intraperitoneal administration of 10 mg/kg of MK 801 blocked the increase of glial parameters and the decrease in content of neuronal marker proteins that occurred as the response to an N-methyl-D-aspartate (NMDA) lesion in the rat hippocampus. The degradation products of GFA protein and the 68-kDa neurofilament polypeptide that were induced by the NMDA lesion did not appear after MK 801 treatment. This study shows that brain-specific proteins are a set of precise tools for the evaluation of neuroprotective effects of antagonists to excitatory amino acids. Topics: Animals; Behavior, Animal; Biomarkers; Body Weight; Brain Diseases; Dizocilpine Maleate; Glial Fibrillary Acidic Protein; Immunoblotting; Intermediate Filament Proteins; Male; Nerve Tissue Proteins; Neuroglia; Neurons; Rats; Rats, Inbred Strains | 1991 |
Delay of puberty and impairment of growth in female rats given a non competitive antagonist of NMDA receptors.
Reportedly, excitatory amino acids are involved in the control of gonadotropin secretion of rats and non-human primates. The aim of this study was to investigate the effect of chronic blockade of NMDA (N-methyl-D-aspartic acid) receptors by the non competitive receptor antagonist MK-801 on gonadotropin secretion and the onset of puberty in female rats. Moreover, since in humans alterations of the timing of puberty frequently coexist with disturbances of body growth, suggesting a common etiology for both events, we evaluated the effect of MK-801 also on the neural mechanisms controlling growth hormone (GH) secretion. Twenty-one-day-old female rats were treated with MK-801 (0.2 mg/kg ip, bid) or placebo for 10 days and were killed after 7 days of withdrawal. Administration of MK-801 induced a significant impairment of growth rate without altering food intake, and a delay in vaginal opening. Pituitaries from rats treated with MK-801 had a reduced luteinizing hormone (LH) content, and secreted in vitro lower amounts of LH both under basal and LHRH-stimulated conditions. MK-801 treated rats had a lower pituitary GH content and basal and GHRH-stimulated GH release and reduced plasma insulin-like growth factor-I levels. These data indicate that blockade of NMDA receptors in a critical period of the female rat life-span: 1) delays puberty by reducing gonadotropin secretion; 2) impairs growth rate by reducing GH secretion, with a mechanism still to be clarified. Topics: Animals; Body Weight; Dizocilpine Maleate; Female; Gonadotropin-Releasing Hormone; Growth; Growth Hormone; Insulin-Like Growth Factor I; Luteinizing Hormone; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Sexual Maturation | 1990 |
Immediate and long-lasting effects of MK-801 on motor activity, spatial navigation in a swimming pool and EEG in the rat.
In a series of experiments, rats received the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 and measures were made of motor behavior, spatial navigation in a swimming pool, and electroencephalographic (EEG) activity. High doses (0.25-10 mg/kg IV) produced somnolence and akinesia, impaired food consumption, locomotion and swimming, and also impaired navigation to a hidden platform but complete recovery on all measures was obtained between 3 and 5 days postinjection. Lower doses (0.05-0.10 mg/kg, IV) impaired acquisition of a new place response in a swimming pool and produced hyperactivity but did not impair performance on a new cue response or on a well-learned place response. Two forms of hippocampal EEG activity, atropine-sensitive and atropine-resistant EEG were present with the low doses. The results demonstrate that a single dose of MK-801 causes changes in motor behavior and learning lasting a few days, but complete recovery occurs within 5 days of administration of even very high doses of MK-801. They further demonstrate that low doses of the drug selectively impair acquisition of new place responses. Although the general changes in behavior produced by MK-801 suggest that NMDA receptors are involved in many aspects of the control of behavior, the results additionally suggest that NMDA receptors are important for place learning. Topics: Animals; Anticonvulsants; Atropine; Body Weight; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroencephalography; Female; Motor Activity; Orientation; Physostigmine; Rats; Reaction Time; Space Perception; Swimming; Time Factors | 1989 |