Cannabinoids activate mesolimbic dopamine neurons by an action on cannabinoid CB1 receptors

The present study was designed to determine if cannabinoids share with other drugs of abuse the ability to stimulate mesolimbic dopaminergic neurons and if this effect is mediated by cannabinoid receptors. To this end, the effects of the prototypical cannabinoid, Delta(9) tetrahydrocannabinal {(-)-trans-(6a R, 10a R)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol}, and the two highly potent synthetic cannabinoids, {(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)-methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl, + (1-naphtalenyl)methanone) WIN 55,212-2 and {(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)-cicloexan-1-ol} CP 55,940, on the spontaneous discharge rate of meso-accumbens dopamine (A(10) dopamine) neurons were studied in rats. The intravenous administration of Delta(9)-tetrahydrocannabinol, WIN 55,212-2 and CP 55,940 (0.0625-1.0 mg/kg) produced a dose-dependent increase in the spontaneous firing of A(10) dopamine neurons both in non-anesthetized and anesthetized rats, with a maximal percent increase of 120, 187 and 155 in non-anesthetized and 33, 102 and 52, respectively, in anesthetized rats. The stimulant response to cannabinoids was suppressed by the specific cannabinoid receptor antagonist (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) SR 141716A, indicating a cannabinoid receptor-mediated effect. These findings support the contention that cannabinoids regulate mesolimbic dopamine transmission and may help to explain the addictive properties of marijuana. (C) 1998 Elsevier Science B.V.