Brain Cannabinoid CB(2) Receptors Modulate Cocaine’s Actions in Mice

The presence and function of cannabinoid CB(2) receptors in the brain have been subject to debate. We report here that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB(2) receptor agonist, dose-dependently inhibits intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens dopamine (DA) in wild-type (WT) and CB(1) receptor-knockout (CB(1)(−/−)), but not CB(2)(−/−), mice. This inhibition is mimicked by GW405833, another CB(2) receptor agonist with a different chemical structure, and is blocked by AM630, a selective CB(2) receptor antagonist. Intra-accumbens JWH133 alone dose-dependently decreases, while intra-accumbens AM630 elevates, extracellular DA and locomotion in WT and CB(1)(−/−) mice, but not in CB(2)(−/−) mice. Intra-accumbens AM630 also blocks the reduction in cocaine self-administration and extracellular DA produced by systemic administration of JWH133. These findings, for the first time, suggest that brain CB(2) receptors modulate cocaine’s rewarding and locomotor-stimulating effects, likely by a DA-dependent mechanism.