Effects of melanocortin receptor activation and blockade on ethanol intake: A possible role for the melanocortin-4 receptor

Background: The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor pro-opiomelanocortin. A growing body of literature suggests that the MC system modulates neurobiological responses to drugs of abuse. Because ethanol has direct effects on central proopiornelanocortin activity, it is possible that MC neuropeptides participate in the control of voluntary ethanol consumption. Here we assessed the possibility that MC receptor (MCR) agonists modulate ethanol intake via the MC3 receptor (MC3R) and/or the MC4 receptor (MC4R) and whether the MCR antagonist AgRP-(83-132) controls ethanol consumption. Methods: Mc3r-deficient (Mc3r(-/-)) and wild-type (Mc3r(+/+)) littermate mice were given intraperitoneal (10 mg/kg) and intracerebroventricular (1.0 mu g ICV) doses of melanotan 11 (MTII), a nonselective MCR agonist. To assess the role of MC4R, C57BL/6J mice were given an 1CV infusion of the highly selective MC4R agonist cyclo(NH-CH2-CH2-CO-HiS-(D)-Phe-Arg-Trp-Glu)-NH2 (1.0 or 3.0 mu g). Finally, naive C57BL/6J mice were given an ICV infusion of AgRP-(83-132) (0.05 and 1.0 mu g). Results: MTII was similarly effective at reducing ethanol drinking in Mc3(-/-)deficient (Mc3(-/-)) and wild-type (Mc3r(+/+)) littermate mice. Furthermore, ICV infusion of the MC4R agonist significantly reduced ethanol drinking, whereas ICV infusion of AgRP-(83-132) significantly increased ethanol drinking in C57BL/6J mice. Neither MTII nor AgRP-(83-132) altered blood ethanol levels at doses that modulated ethanol drinking. Conclusions: The present results suggest that MC4R, and not MC3R, modulates MCR agonist-induced reduction of ethanol consumption and that ethanol intake is increased by the antagonistic actions of AgRP-(83-132). These findings strengthen the argument that MCR signaling controls ethanol consumption and that compounds directed at MCR may represent promising targets for treating alcohol abuse disorders in addition to obesity.