cgp-37849 and Disease-Models--Animal

The purpose of this study was to determine how the activation of different regulatory domains of the NMDA complex affects the antianxiety effect of antagonists acting at its distinct binding sites.. The anxiolytic-like activity was assessed by the elevated plus-maze test in mice.. The anxiolytic activity of CGP 37849 (a competitive NMDA receptor antagonist) and L-701,324 (an antagonist at glycine site) was confirmed, but effects of both were significantly reduced by N-methyl-D-aspartic acid (NMDA) or by D-serine agonists at glutamate and glycine site of the NMDA receptor complex, respectively.. The obtained data suggest that stimulation of the glutamate or glycine recognition site of the NMDA receptor complex significantly decreases the antianxiety properties of antagonists of either site.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Binding Sites; Brain; Disease Models, Animal; Drug Interactions; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Ligands; Male; Maze Learning; Mice; N-Methylaspartate; Quinolones; Receptors, N-Methyl-D-Aspartate; Serine

Mesial temporal lobe epilepsy (MTLE) is characterized by focal seizures, associated with hippocampal sclerosis, and often resistance to antiepileptic drugs. The parafascicular nucleus (PF) of the thalamus is involved in the generation of physiological oscillatory rhythms. It receives excitatory inputs from the cortex and inhibitory inputs from the basal ganglia, a system implicated in the control of epileptic seizures. The aim of this study was to examine the involvement of the PF in the occurrence of hippocampal paroxysmal discharges (HPDs) in a chronic animal model of MTLE in male mice. We recorded the local field potential (LFP) and the extracellular and intracellular activity of hippocampal and PF neurons during spontaneous HPDs in vivo. The end of the HPDs was concomitant with a slow repolarization in hippocampal neurons leading to an electrical silence. In contrast, it was associated in the PF with a transient increase in the power of the 10-20 Hz band in LFPs and a depolarization of PF neurons resulting in a sustained firing. We tested the role of the PF in the control of HPDs by single 130 Hz electrical stimulation of this nucleus and bilateral intra-PF injection of NMDA and GABA(A) antagonist and agonist. High-frequency PF stimulation interrupted ongoing HPDs at an intensity devoid of behavioral effects. NMDA antagonist and GABA(A) agonist suppressed hippocampal discharges in a dose-dependent way, whereas NMDA agonist and GABA(A) antagonist increased HPDs. Altogether, these data suggest that the PF nucleus plays a role in the modulation of MTLE seizures.

Topics: 2-Amino-5-phosphonovalerate; Action Potentials; Animals; Biophysical Phenomena; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy, Temporal Lobe; Evoked Potentials, Somatosensory; Excitatory Amino Acid Antagonists; Functional Laterality; GABA-A Receptor Agonists; Hippocampus; Intralaminar Thalamic Nuclei; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Muscimol; N-Methylaspartate; Neurons; Statistics, Nonparametric; Time Factors; Wakefulness

The malfunction of glutamatergic neurotransmission in the neonatal or postnatal periods may be a risk factor for the appearance of neuroanatomical, neurochemical or functional changes that are characteristic of schizophrenia. Thus, the present study was undertaken to investigate whether blockade of N-methyl-d-aspartate (NMDA) receptors in the postnatal period influences rat behavior in tests characterizing schizophrenia-like deficits such as psychomotor agitation, impairments of sensorimotor gating, working memory, and intensity of social interactions. (E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), a competitive antagonist of NMDA receptors, was given postnatally (1.25 mg/kg on days 1, 3, 6, 9; 2.5 mg/kg on days 12, 15, 18; and finally 5 mg/kg on day 21, all injections s.c.), and rats were tested at 60 days old. We found that blockade of NMDA receptors in the postnatal period led to an enhancement of exploration, mimicking psychomotor agitation, impairments in sensorimotor gating as measured by a prepulse-evoked inhibition of acoustic startle response, and an impaired working memory, as measured by an increase in the latency to achieve accurate rate of response in the delayed alternation task. Decreases in non-aggressive social interactions and increases in aggressive interactions were also observed. In addition to cognitive deficits typical of schizophrenia, rats treated postnatally with NMDA receptor antagonists also showed higher level of fear exhibited in the elevated plus maze. Thus, the blockade of NMDA receptors in the postnatal period may model deficits that are characteristic of schizophrenia.

Topics: 2-Amino-5-phosphonovalerate; Age Factors; Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Exploratory Behavior; Female; Male; Maze Learning; Phencyclidine; Pregnancy; Psychomotor Performance; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Schizophrenia; Social Behavior

The present study assessed whether the blockade of NMDA receptors in the postnatal period, used to model the symptoms of schizophrenia altered morphology of pyramidal neurons in the medial prefrontal cortex of rats. CGP 40116, an antagonist of NMDA receptors, was given postnatally (days 1-21 after birth). The analysis of the morphology of pyramidal neurons visualized by the Golgi-Cox technique revealed that the exposure to an antagonist of NMDA receptors in the postnatal period diminished the length of basilar dendrites, while that of apical dendrites remained unchanged. The number of dendritic branches and the spine density remained unchanged. It is concluded that the blockade of NMDA receptors in the postnatal period only partially models morphological changes in pyramidal neurons of the medial prefrontal cortex, which are observed in some cases of schizophrenia.

Topics: 2-Amino-5-phosphonovalerate; Animals; Animals, Newborn; Cell Count; Dendrites; Disease Models, Animal; Excitatory Amino Acid Antagonists; Female; Male; Organ Size; Prefrontal Cortex; Pyramidal Cells; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Sound-induced seizures in genetically epilepsy-prone rats were used to compare the anticonvulsant effect of phenytoin and diazepam with compounds which decrease glutamatergic neurotransmission including excitatory amino acid antagonists acting at N-methyl-D-aspartate (NMDA) receptors: D(-)CPPene, CGP 37849 and MK 801 or at the glycine/NMDA site: ACPC (1-aminocyclopropane-dicarboxylic acid) (partial agonist) or non-NMDA receptors: NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]-quinoxaline.Li) and GYKI 52466 (1-(aminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepin e.HCl) or acting at sodium channels to decrease glutamate release: lamotrigine and BW 1003C87 (5(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine ethane sulphonate). ED50 values against clonic seizures (in mumol/kg at the time of peak anticonvulsant effect) were: phenytoin 30.5 (2 h), diazepam 0.5 (0.5 h), MK 801 0.01 (4 h), D(-)CPPene 1.9 (4 h), CGP 37849 2 (1 h), GYKI 52466 24 (0.25 h), NBQX 40 (0.5 h), ACPC 1053 (0.5 h), BW 1003C87 2.2 (1 h), lamotrigine 4.8 (4 h). BW 1003C87, lamotrigine, MK 801, phenytoin, diazepam and CGP 37849 had the most favourable therapeutic indices (rotarod locomotor deficit ED50/anticonvulsant ED50).

Topics: 2-Amino-5-phosphonovalerate; Acoustic Stimulation; Amino Acids; Amino Acids, Cyclic; Analysis of Variance; Animals; Anticonvulsants; Behavior, Animal; Diazepam; Disease Models, Animal; Dizocilpine Maleate; Epilepsy; Female; Lamotrigine; Male; Motor Activity; Phenytoin; Pyrimidines; Quinoxalines; Rats; Rats, Sprague-Dawley; Time Factors; Triazines