Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects

The cannabinoid CB1 receptor has been shown to be the primary site of actio n for cannabinoid-induced effects on the central nervous system. Activation of this receptor has proven to dampen neurotransmission and produce an ove rall reduction in neuronal excitability. Cannabinoid compounds like Delta ( 9)-tetrahydrocannabinol and cannabidiol have been shown to be anticonvulsan t in maximal electroshock, a model of partial seizure with secondary genera lization. However, until now, it was unknown if these anticonvulsant effect s are mediated by the cannabinoid CB1 receptor. Likewise, (R)-(+)-[2,3-Dihy dro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]- 1-naphthalenylmethanone (WIN 55,212-2), a cannabimimetic compound that has been shown to decrease hyperexcitability in cell culture models via the can nabinoid CB1 receptor, has never been evaluated for anticonvulsant activity in an animal seizure model. We first show that the cannabinoid compounds D elta (9)-tetrahydrocannabinol (ED50 = 42 mg/kg), cannabidiol (ED50 = 80 mg/ kg), and WIN 55,212-2 (ED50 47 mg/kg) are anticonvulsant in maximal electro shock. We further establish, using the cannabinoid CB1 receptor specific an tagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-meth yl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) (AD(50) = 2.5 mg/kg), that the anticonvulsant effects of Delta (9)-tetrahydrocannabinol and WIN 55,212-2 are cannabinoid CB1 receptor-mediated while the anticonvulsant act ivity of cannabidiol is not. This study establishes a role for the cannabin oid CB1 receptor in modulating seizure activity in a whole animal model. (C ) 2001 Elsevier Science B.V. All rights reserved.