MTII-induced reduction of voluntary ethanol drinking is blocked by pretreatment with AgRP-(83-132).

Over the last 30 years, evidence has emerged indicating that the central melanocortin (MC) peptide system is involved with neurobiological responses to drugs of abuse. Recently, rats selectively bred for high ethanol preference were shown to have altered brain levels of MC receptor (MCR) and central infusion of the potent non-selective MCR agonist, melanotan-II (MTII), attenuates their high ethanol drinking. The goal of the present report was to further characterize the effects of MTII on voluntary ethanol consumption. In alcohol preferring C57BL/6 mice with an established history of ethanol drinking, intracerebroventricular (i.c.v.) infusion of a 5.0 microg dose of agouti-related protein (AgRP)-(83-132), a non-selective MCR antagonist, has no effect on 8-h ethanol drinking or food intake. However, pre-treatment with a 5.0 microg dose of (AgRP)-(83-132) significantly blocks MTII-induced (1.0 microg) reduction of 8-h ethanol drinking and food intake, consistent with a competitive antagonist action. I.c.v. infusion of MTII does not cause alteration of blood ethanol levels 2- or 4-h following intraperitoneal (i.p.) injection of a 4.0 g ethanol/kg dose. Finally, when given in an i.p. injection, a 150 microg dose of MTII reduces 8-h ethanol drinking. These data extend recent findings by showing that both central and peripheral administration of MTII reduces ethanol drinking by mice. Additionally, the ability of (AgRP)-(83-132) to block the effects of MTII implies that MTII-induced reduction of ethanol drinking is receptor mediated.