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.