Assessment of the role of CB receptors in cannabinoid 1 anticonvulsant effects

The cannabinoid CB receptor has been shown to be the primary site of action for cannabinoid-induced effects on the central nervous 1 system. Activation of this receptor has proven to dampen neurotransmission and produce an overall reduction in neuronal excitability. Cannabinoid compounds like D-tetrahydrocannabinol and cannabidiol have been shown to be anticonvulsant in maximal electroshock, a model of partial seizure with secondary generalization. However, until now, it was unknown if these anticonvulsant effects are mediated Ž . Ž . w Ž . w x by the cannabinoid CB receptor. Likewise, R q 2,3-Dihydro-5-methyl-34-morpholinylmethyl pyrrolo 1,2,3-de -1,4-benzoxazin-61 x Ž . yl -1-naphthalenylmethanone WIN 55,212-2 , a cannabimimetic compound that has been shown to decrease hyperexcitability in cell culture models via the cannabinoid CB receptor, has never been evaluated for anticonvulsant activity in an animal seizure model. We 1 9 Ž . Ž . first show that the cannabinoid compounds D -tetrahydrocannabinol ED s42 mgrkg , cannabidiol ED s80 mgrkg , and WIN 50 50 Ž . 55,212-2 ED s47 mgrkg are anticonvulsant in maximal electroshock. We further establish, using the cannabinoid CB receptor 50 1 Ž Ž . Ž . specific antagonist Npiperidin-1-yl-54-chlorophenyl -12,4-dichlorophenyl -4-methyl-1H-pyrazole-3-carboxamidehydrochloride Ž . Ž . 9 SR141716A AD s2.5 mgrkg , that the anticonvulsant effects of D -tetrahydrocannabinol and WIN 55,212-2 are cannabinoid CB 50 1 receptor-mediated while the anticonvulsant activity of cannabidiol is not. This study establishes a role for the cannabinoid CB receptor in 1 modulating seizure activity in a whole animal model. q 2001 Elsevier Science B.V. All rights reserved.