Brain cannabinoid CB₂ receptors modulate cocaine's actions in mice

The presence and function of cannabinoid CB₂ receptors in the brain have been the subjects of much debate. We found that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB₂ receptor agonist, dose-dependently inhibited intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens extracellular dopamine in wild-type and CB₁ receptor knockout (CB 1 also known as Cnr1 mice, but not in CB₂ (Cnr2 ) mice. This inhibition was mimicked by GW405833, another CB 2 receptor agonist with a different chemical structure, and was blocked by AM630, a selective CB₂ receptor antagonist. Intra-accumbens administration of JWH133 alone dose-dependently decreased, whereas intra-accumbens administration of AM630 elevated, extracellular dopamine and locomotion in wild-type and CB 1 mice, but not in CB₂ mice. Intra-accumbens administration of AM630 also blocked the reduction in cocaine self-administration and extracellular dopamine produced by systemic administration of JWH133. These findings suggest that brain CB 2 receptors modulate cocaine's rewarding and locomotor-stimulating effects, likely by a dopamine-dependent mechanism.