Nicotinic facilitation of delta-9-tetrahydrocannabinol discrimination involves endogenous anandamide

Increasing use of cannabis makes the search for medications to reduce cannabis abuse extremely important. Here, we show that homomeric alpha(7) nicotinic receptors are novel molecular entities that could be targeted in the development of new drugs for the treatment of cannabis dependence. In rats, systemic administration of the selective alpha 7 nicotinic acetylcholine receptor antagonist methyllycaconitine ( MLA), but not the selective heteromeric non-alpha(7) nicotinic acetylcholine receptor antagonist dihydrobetaerythroidine, ( 1) antagonized the discriminative effects of delta-9-tetrahydrocannabinol ( THC), the main active ingredient in cannabis, ( 2) reduced intravenous self-administration of the synthetic cannabinoid CB1 receptor agonist WIN55,212-2 [( R)-( +)-[ 2,3-dihydro-5-methyl-3[( 4-morpholinyl)methyl] pyrrolo[ 1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone, mesylate salt], and ( 3) decreased THC-induced dopamine elevations in the shell of the nucleus accumbens. Altogether, our results indicate that blockade of alpha(7) nicotinic receptors reverses abuse-related behavioral and neurochemical effects of cannabinoids. Importantly, MLA reversed the effects of cannabinoids at doses that did not produce depressant or toxic effects, further pointing to alpha(7) nicotinic antagonists as potentially useful agents in the treatment of