Role of the melanocortin-4 receptor in mediating cocaine reward.

摘要

The melanocortin-4 receptor, a G-protein coupled receptor that stimulates adenylate cyclase and cAMP production in response to α-MSH and ACTH, is the most abundant subtype of melanocortin receptor found in the brain. This subtype is especially enriched in the striatum and nucleus accumbens, areas of the brain recognized to be involved in the etiology of drug addiction. Repeated administration of cocaine regulates the expression of MC4-R, but not MC3-R, in rat striatum and nucleus accumbens. Based on this and previous studies indicating the regulation of this receptor by drugs of abuse, the possibility that this receptor might be involved in drug addiction, in particular cocaine addiction, was examined. Locomotor sensitization studies show that blockade of the MC4-R results in a reduced development of locomotor sensitization to cocaine in both Ay (Agouti) and MC4R-KO mice in a gene-dosage dependant manner. In addition, rats receiving SHU9119 (a synthetic antagonist at the MC4-R) pretreatment displayed disruption in cocaine-induced locomotor sensitization. In cocaine-induced conditioned place preference (CPP) experiments, disruptions in melanocortinergic signaling similarly resulted in disruptions in behavior. SHU9119 treatment (1 μg bilateral nucleus accumbens infusion) completely blocked cocaine (10 mg/kg) induced CPP in rats in two separate and distinct phases, acquisition and expression. SHU9119 alone was shown not to have an aversive effect. However, CPP experiments performed in MC4-R knockout mice did not result in statistically significant disruptions in cocaine conditioned place preference in the knockout mice versus wild-type littermates. We next studied the effect of SHU9119 on cocaine self-administration in rats. Infusion of SHU9119 directly into the rat accumbens resulted in reduction of cocaine self-administration in an antagonist dosage-dependant manner. Maximum reduction in self-administration responses (at 0.5 mg cocaine per kg per infusion) was achieved with antagonist doses greater than 0.50 μg in 0.5 μ1 PBS (bilateral accumbens infusion). The effect of this disruption in cocaine self-administration can be overcome by larger doses of cocaine. To investigate the molecular mechanisms underlying this disruption in cocaine-induced behavioral responses, co-localization studies were performed, and indicated a high degree of co-localization with MC4-R and dynorphin. This suggests that melanocortin signaling may exert effects on drug addiction behaviors through D₁ receptor-mediated pathways. The results of these studies provide further support that the MC4-R plays a significant role in mediating the rewarding properties of cocaine.