The melanocortin system as a potential target for treating alcohol use disorders: A review of pre-clinical data

Abstract

The melanocortin (MC) system consists of neuropeptides that are cleaved from the polypeptide precursor proopiomelanocortin (POMC). In the brain, MC neuropeptides signal primarily through the MC-3 and MC-4 receptors, which are widely expressed throughout the brain. While the MC system has been largely studied for its role in food intake and body weight regulation, converging evidence has emerged over approximately the last 20-years showing that alcohol (ethanol), and other drugs of abuse influence the central MC system, and that manipulating MC receptor signalling modulates ethanol intake. Although there is divergent evidence, the wealth of data appears to suggest that activating MC signalling, primarily through the MC-4 receptor, is protective against excessive ethanol consumption. In the present review, we first describe the MC system and then detail how ethanol exposure and consumption alters central MC and MC-receptor expression and levels. This is followed by a review of the data, from pharmacological and genetic studies, which show that manipulations of MC receptor activity alter ethanol intake. We then briefly highlight studies implicating a role for the MC system in modulating neurobiological responses and intake of other drugs of abuse, including amphetamine, cocaine and opioids. Finally, we introduce relatively new observations that the drug, bupropion (BUP), a drug that activates central MC activity, significantly reduces ethanol intake in rodent models when administered alone and in combination with the non-selective opioid receptor antagonist, naltrexone. Phase II clinical trials are currently underway to assess the efficacy of BUP as a treatment for alcohol use disorders.

Keywords: Agouti-related protein; Alcohol; Bupropion; MC-4 receptor; Melanocortin; Naltrexone.