The protective effects of the melanocortin receptor (MCR) agonist, melanotan-II (MTII), against binge-like ethanol drinking are facilitated by deletion of the MC3 receptor in mice.

Recent data have implicated the melanocortin (MC) system in modulating voluntary ethanol consumption. Administration of melanotan-II (MTII), a nonselective melanocortin receptor (MCR) agonist, reduces voluntary ethanol consumption in C57BL/6J mice. Previous studies have demonstrated that central infusion of MTII effectively reduced voluntary ethanol drinking in mutant mice lacking normal expression of MC3R (MC3R-/- mice) but failed to alter ethanol drinking in mice lacking expression of MC4R, demonstrating that central MTII administration reduces voluntary ethanol drinking by signaling through the MC4R. However, evidence shows that the neurocircuitry recruited during excessive binge-like ethanol drinking versus moderate ethanol drinking are not identical. Thus the present study sought to investigate the potential role of the MC3R in binge-like ethanol intake. To this end, the "drinking in the dark" (DID) procedure, a commonly used animal model of binge-like ethanol drinking, was employed. Wild-type MC3R+/+ and MC3R-/- mice were given intracerebroventricular (i.c.v.) infusion of MTII (0.0, 0.25, 0.50, or 1.0 μg) prior to the onset of a 4-h testing period in which mice were given access to 20% (v/v) ethanol. Immediately after the 4-h testing period, tail blood samples were collected from each animal in order to assess blood ethanol concentrations (BECs). Consistent with previous findings, central administration of MTII blunted binge-like ethanol drinking in both MC3R+/+ and MC3R-/- mice. Interestingly, all doses of MTII blunted binge-like ethanol drinking in MC3R-/- mice during the first hour of testing, while only the 1.0 μg dose reduced binge-like drinking in MC3R+/+ mice. Thus, MC3R-/- mice were more sensitive to the protective effects of MTII. These data suggest that MC3Rs oppose the protective effects of MTII against binge-like ethanol drinking, and thus selective MC3R antagonists may have potential therapeutic roles in treating excessive ethanol drinking.