ORIGINAL PAPER Modulation of Anticonvulsant Effects of Cannabinoid Compounds by GABA-A Receptor Agonist in Acute Pentylenetetrazole Model of Seizure in Rat Nima Naderi • Leila Ahmad-Molaei • Farzad Aziz Ahari • Fereshteh Motamedi Accepted: 15 April 2011 / Published online: 23 April 2011 Ó Springer Science+Business Media, LLC 2011 Abstract Cannabinoid system plays an important role in controlling neuronal excitability and brain function. On the other hand, modulation of gamma-aminobutyric acid (GABA) transmission is one of the initial strategies for the treatment of seizure. The aim of the present study was to evaluate possible interaction between cannabinoidergic and GABAergic systems in pentylenetetrazole (PTZ)-induced acute seizure in rat. Drugs were administered by intracer- ebroventricular (i.c.v.) administration 20 min before a single intraperitoneal (i.p.) injection of PTZ and the latency to the first generalized tonic-clonic seizure was measured. Both the cannabinoid receptor agonist WIN55212-2 (10, 30, 50 and 100 lg/rat) and the GABA-A receptor agonist isoguvacine (IGN; 10, 30 and 50 lg/rat) significantly increased the latency of seizure occurrence. Moreover, the fatty acid amide hydrolase inhibitor URB597 showed no anticonvulsive effect while the monoacyl glycerol lipase (MAGL) inhibitor URB602 (10, 50 and 100 lg/rat) protected rats against PTZ-induced seizure. Moreover, co-administration of IGN and cannabinoid compounds attenuated the anticonvulsant action of both WIN55212-2 and IGN in this model of seizure. Our data suggests that exogenous cannabinoid WIN55212-2 and MAGL inhibitor URB602 imply their antiseizure action in part through common brain receptorial system. Moreover, the antago- nistic interaction of cannabinoids and IGN in protection against PTZ-induced seizure could suggest the involve- ment of GABAergic system in their anticonvulsant action. Keywords Seizure Á Pentylenetetrazole (PTZ) Á Cannabinoid Á GABA-A Á Rat Introduction Seizure is a transient occurrence of signs and symptoms due to abnormal excessive or synchronous neuronal activity in the brain [1]. Several lines of studies have indicated sub- stantial role of cannabinoidergic system in basal neural excitability and related pathological condition in central nervous system; however, their underlying mechanisms and relationship with seizure initiation remain unknown. In this regard, the anticonvulsant activity of cannabinoid com- pounds has been shown in different experimental seizure models as well as in epileptic patients [2–4]. The neuro- modulatory effect of cannabinoid compounds is mediated through both cannabinoid and non-cannabinoid receptors. In this regard, exogenous cannabinoid compounds, endoge- nous ligands (endocannabinoids) such as anandamide and 2-arachidonoyl-glycerol (2-AG) as well as the enzymatic machinery for their biosynthesis, transport and degradation are possible target components for affecting this system [5]. Many investigations have shown that alteration in CB1 distribution occurred following epilepsy, demonstrating the compensatory role of endocannabinoid in ameliorating excessive excitability in the epilepsy both in human [6] and in animal models of seizure [3]. On the other hand, GAB- Aergic system, through GABA-A receptor, play important role in the pathogenesis and amelioration of seizure and [7] many of the drugs that enhance GABAergic neurotrans- mission in the brain have been shown to be clinically active anticonvulsants [7]. It was demonstrated that both iso- guvacine (IGN), which activates GABA-A receptors directly and diazepam, which enhances GABA-A-mediated N. Naderi (&) Á L. Ahmad-Molaei Á F. Aziz Ahari Á F. Motamedi Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, P.O. Box 19615-1178, Tehran, Iran e-mail: naderi@sbmu.ac.ir 123 Neurochem Res (2011) 36:1520–1525 DOI 10.1007/s11064-011-0479-1