Although the activation of CB1-receptor by cannabinoids and block of NMDA receptors are known to decrease seizure severity in epilepsy models, the interaction between these systems remain elusive. Therefore, the present study was initiated to evaluate the possible interactions between cannabinoid compounds and NMDA receptor antagonist in the penicillin-induced epileptiform activity in rat. In the first set of experiments, 30 min after intracortical injection of penicillin, five different doses of memantine (3,5-dimethyl-1-adamantanamine hydrochloride, 1, 2.5, 5, 10 or 20 mg/kg) were administered intraperitoneally (i.p.). In the second set of experiments, intracerebroventricular (i.c.v.) AM-251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], (0.25 mu g) a CB1-receptor antagonist and ACEA (arachidonyl-2-chloroethylamide), (7.5 mu g) a CB1-receptor agonist, were administered 15 min after memantine (i.p.) application. Memantine, NMDA receptor antagonist, at doses of 2.5 and 5 mg/kg (i.p.) decreased the mean frequency of penicillin-induced epileptiform activity with a maximal effect at 5 mg/kg. Memantine, at the lowest dose (1 mg/kg, i.p.) and highest doses (10 and 20 mg/kg, i.p.) did not change the frequency of epileptiform activity. ACEA, at a dose of 7.5 mu g, also decreased the frequency of epileptiform activity, whereas AM-251, at a dose of 0.25 mu g increased the frequency by causing status epilepticus-like activity. The best and earlier anti-epileptiform effects appeared in both the presence of memantine (5 mg/kg, i.p.) and ACEA (7.5 mu g, i.c.v.), which was blocked by CB1-receptor antagonist, AM-251. The results of the present study provide electrophysiologic evidence for an interaction between cannabinoid system and NMDA receptors, probably via NMDA-mediated Ca2+ influx in the penicillin-induced epilepsy. (C) 2010 Elsevier B.V. All rights reserved.