Background The nonselective opioid receptor antagonist, naltrexone (NAL), reduces alcohol (ethanol [EtOH]) consumption in animals and humans and is an approved medication for treating alcohol abuse disorders. Proopiomelanocortin (POMC)‐derived melanocortin (MC) and opioid peptides are produced in the same neurons in the brain, and recent preclinical evidence shows that MC receptor (MCR) agonists reduce excessive EtOH drinking in animal models. Interestingly, there is a growing body of literature revealing interactions between the MC and the opioid systems in the modulation of pain, drug tolerance, and food intake.

Methods In the present report, a mouse model of binge EtOH drinking was employed to determine whether the MCR agonist, melanotan‐II (MTII), would improve the effectiveness of NAL in reducing excessive binge‐like EtOH drinking when these drugs were co‐administered prior to EtOH access.

Results Both NAL and MTII blunt binge‐like EtOH drinking and associated blood EtOH levels, and when administered together, a low dose of MTII (0.26 mg/kg) produces a 7.6‐fold increase in the effectiveness of NAL in reducing binge‐like EtOH drinking. Using isobolographic analysis, it is demonstrated that MTII increases the effectiveness of NAL in a synergistic manner.