Cocaine is a highly addictive drug that acts upon the brain’s reward circuitry via the inhibition of monoamine uptake.

Endogenous cannabinoids (eCB) are lipid molecules released from midbrain dopamine (DA) neurons that modulate cocaine’s effects through poorly understood mechanisms.

Researchers find that cocaine stimulates release of the eCB, 2-arachidonoylglycerol (2-AG), in the rat ventral midbrain to suppress GABAergic inhibition of DA neurons, through activation of presynaptic cannabinoid CB1 receptors.

Cocaine mobilizes 2-AG via inhibition of norepinephrine uptake and promotion of a cooperative interaction between G_q/11-coupled type-1 metabotropic glutamate and α₁-adrenergic receptors to stimulate internal calcium stores and activate phospholipase C.

The disinhibition of DA neurons by cocaine-mobilized 2-AG is also functionally relevant because it augments DA release in the nucleus accumbens in vivo.

These results identify a mechanism through which the eCB system can regulate the rewarding and addictive properties of cocaine.