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 20mg/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 μg) a CB1-receptor antagonist and ACEA (arachidonyl-2-chloroethylamide), (7.5 μg) a CB1-receptor agonist, were administered 15 min after
memantine (i.p.) application.
Memantine,
NMDA receptor antagonist, at doses of 2.5 and 5mg/kg (i.p.) decreased the mean frequency of
penicillin-induced epileptiform activity with a maximal effect at 5mg/kg.
Memantine, at the lowest dose (1mg/kg, i.p.) and highest doses (10 and 20mg/kg, i.p.) did not change the frequency of epileptiform activity. ACEA, at a dose of 7.5 μg, also decreased the frequency of epileptiform activity, whereas
AM-251, at a dose of 0.25 μg increased the frequency by causing
status epilepticus-like activity. The best and earlier anti-epileptiform effects appeared in both the presence of
memantine (5mg/kg, i.p.) and ACEA (7.5 μg, 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 Ca(2+) influx in the
penicillin-induced
epilepsy.