Dysregulation of cannabinoid CB1 receptor and associated signaling networks in brains of cocaine addicts and cocaine-treated rodents.

The endocannabinoid system is implicated in the neurobiology of cocaine addiction. This study evaluated the status of cannabinoid (CB) CB1 and CB2 receptors, the endocytic cycle of CB1 receptors, G protein-coupled receptor regulatory kinases (GRK), and associated signaling (mammalian target of rapamicin (mTOR) and 70kDa ribosomal protein S6 kinase (p70S6K)) in brain cortices 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 (PFC) 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% to -30%) indicated receptor desensitization. CB2 receptor protein was not significantly altered in the PFC 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.