(+/-)Baclofen sensitive scopolamine-induced short-term memory deficits in mice.

Possible involvement of GABA receptor systems in scopolamine-induced short-term memory deficits was investigated using latency of mice to reach shock-free zone (SFZ) and number of mistakes (descents) the animal made in 15 min as parameters for acquisition and retention of memory in passive avoidance paradigm. Atropine (1-5 mg/kg), scopolamine (0.1-0.5 mg/kg) but not pirenzepine (5-20 mg/kg) caused disruption of memory. GABA (50, 75 and 100 mg/kg) showed retention enhancing effects in scopolamine-treated and untreated animals but GABA agonist progabide (5-20 mg/kg) did not affect any of the parameter significantly. GABAA agonist, muscimol (0.05 and 0.1 mg/kg) and GABAB agonist, (+/-)baclofen (0.25, 0.5 and 1 mg/kg) and (-)baclofen (0.25 and 0.5 mg/kg) also displayed memory enhancing action. Whereas, GABAA antagonist, bicuculline produced hind limb rigidity, GABAB antagonist, CGP 35348 did not show any effect per se, but reversed the (+/-)baclofen-induced delay in latency, without affecting retention enhancing action of (+/-)baclofen. Combined administration of subeffective dose of GABA (50 mg/kg) and (+/-)baclofen (0.25 mg/kg), showed a significant improvement in acquisition and retention. However, the effect of GABA (100 mg/kg) on acquisition was reversed by bicuculline (2 mg/kg) and by CGP 35348 (100 mg/kg) while improving retention. The present study extends support to the cholinergic concept in cognitive performance and provide an evidence for the influence of GABAergic (particularly GABAB) modulation in scopolamine-induced learning and memory deficits in mice.

Evidence for benzodiazepine receptor interaction with MK 801 in anxiety related behaviour in rats.

Antianxiety effect of noncompetitive NMDA receptor antagonist MK 801 was investigated on elevated plus-maze paradigm in rats. Interactional effects of MK 801 with the specific anxiolytic agent, diazepam; the anxiogenic beta-carboline agent, FG-7142 and the central BZ receptor antagonist Ro 15-1788 were explored. MK 801 (0.025-0.1 mg/kg) produced anxiolytic effect at all the doses in rats. Effect was potentiated by diazepam in rats. Both, FG-7142 and Ro 15-1788 reversed the effects of MK 801 and diazepam, when these agents were concomitantly administered. The study revealed anxiolytic profile of MK 801 and indicates that NMDA receptors can modulate the benzodiazepine receptor activity in rodents in elevated plus-maze apparatus.

Effect of NMDA-receptor ligands on neocortical and hippocampal EEG activity of rat brain.

Neocortex and hippocampus play important role in motor activity, neuronal plasticity and learning and memory mechanisms. Electroencephalographic (EEG) activity of neocortex and hippocampus of rat following NMDA-receptor agonist, N-methyl-D-aspartate (NMDA), 0.25-2 nmol in 10 microliters, ICV and noncompetitive NMDA-receptor antagonists, MK 801 (0.025-0.1 mg/kg, ip) and ketamine (10-50 mg/kg, ip) at OH, 1/2H, 4H, 8H and 24H was recorded. The electrodes were implanted stereotaxically in hippocampus and neocortex respectively. NMDA (0.25 and 1 nmol) showed longer lasting decrease in amplitude in hippocampus and in frequency in cortical neurons while 2 nmol produced epileptogenic neurotoxicity. Opposite effect i.e. increase in amplitude in both, hippocampus and neocortex was observed with MK 801 and ketamine and these agents also showed longer lasting influence. Administration of MK 801 (0.05 mg/kg) and ketamine (50 mg/kg) prior to NMDA 2 nmol protected 40% animals from NMDA-induced neurotoxicity and blockade of NMDA-induced long term influence. The EEG effect of NMDA agonist and NMDA-induced neurotoxicity at higher dose and its modification by NMDA-antagonist, MK 801 and ketamine suggest that beside NMDA agonists (NMDA), its antagonists may, also affect long lasting changes in hippocampus and cortex. These antagonists reverse NMDA-mediated long term influence in these brain areas.

Dizocilpine, ketamine and ethanol reverse NMDA-induced EEG changes and convulsions in rats and mice.

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