Epilepsy Research (2011) 93, 128—137 journal homepage: www.elsevier.com/locate/epilepsyres The effect of co-administration of the NMDA blocker with agonist and antagonist of CB1-receptor on penicillin-induced epileptiform activity in rats Duygu Cakil a , Mehmet Yildirim b , Mustafa Ayyildiz a , Erdal Agar a,* a Department of Physiology, Faculty of Medicine, University of Ondokuz Mayis, 55139 Samsun, Turkey b Department of Physiology, Faculty of Medicine, Karadeniz Technical University, 61080 Trabzon, Turkey Received 11 June 2010; received in revised form 23 November 2010; accepted 25 November 2010 Available online 21 December 2010 KEYWORDS AM-251; ACEA; Cannabinoids; Epilepsy; NMDA; Memantine; Penicillin Summary Although the activation of CB1-receptor by cannabinoids and block of NMDA recep- tors 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 g) a CB1-receptor antagonist and ACEA (arachidonyl-2-chloroethylamide), (7.5 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 fre- quency of epileptiform activity. ACEA, at a dose of 7.5 g, also decreased the frequency of epileptiform activity, whereas AM-251, at a dose of 0.25 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 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 Ca 2+ influx in the penicillin-induced epilepsy. © 2010 Elsevier B.V. All rights reserved. ∗ Corresponding author. Tel.: +90 362 312 1919x2223; fax: +90 362 457 6041. E-mail address: eragar@omu.edu.tr (E. Agar). 0920-1211/$ — see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2010.11.008