The endocannabinoid system is implicated in the neurobiology of cocaine addiction. This study evaluated the status of cannabinoid CB₁ and CB₂ receptors, the endocytic cycle of CB₁ receptors, receptor regulatory kinases (GRK), and associated signaling (mTOR and p70S6K) in brain cortex of drug abusers and cocaine- and cannabinoid-treated rodents. The main results indicate that in cocaine adddicts, but not in mixed cocaine/opiate or opiate abusers, CB₁ receptor protein in the prefrontal cortex was reduced (-44%, total homogenate) with a concomitant receptor redistribution and/or internalization (decreases in membranes and increases in cytosol). In cocaine addicts, the reductions of CB₁ receptors and GRK2/3/5 (-26-30%) indicated receptor desensitization. CB₂ receptor protein was not significantly altered in the prefrontal cortex of cocacine addicts. Chronic cocaine in mice and rats also reduced CB₁ receptor protein (-41% and -80%) in the cerebral cortex inducing receptor redistribution and/or internalization. The CB₁ receptor agonist WIN55212-2 caused receptor downregulation (decreases in membranes and cytosol) and the antagonists rimonabant and AM281 induced opposite effects (receptor upregulation in membranes and cytosol). Rimonabant and AM281 also behaved as inverse agonists on the activation of mTOR and its target p70S6K. Chronic cocaine in mice was associated with tolerance to the acute activation of mTOR and p70S6K. In long-term cocaine addicts, mTOR and p70S6K activations were not altered when compared with controls, indicating that CB₁ receptor signaling was dampened. The dysregulation of CB₁ receptor, GRK2/3/5, and mTOR/p70S6K signaling by cocaine may contribute to alterations of neuroplasticity and/or neurotoxicity in brains of cocaine addicts.
Copyright © 2013. Published by Elsevier Ltd.