Lateral hypothalamic melanocortin receptor signaling modulates binge-like ethanol drinking in C57BL/6J mice

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Abstract

Binge ethanol drinking is a highly pervasive and destructive behavior yet the underlying neurobiological mechanisms remain poorly understood. Recent work suggests that overlapping neurobiological mechanisms modulate feeding disorders and excessive ethanol intake, and converging evidence indicates that the melanocortin (MC) system may be a promising candidate. The aims of the present work were to examine how repeated binge-like ethanol drinking, using the ‘drinking in the dark’ (DID) protocol, impacts key peptides within the MC system and if site-specific manipulation of MC receptor (MCR) signaling modulates binge-like ethanol drinking. Male C57BL/6J mice were exposed to one, three or six cycles of binge-like ethanol, sucrose or water drinking, after which brain tissue was processed via immunohistochemistry (IHC) for analysis of key MC peptides, including alpha-melanocyte stimulating hormone (α-MSH) and agouti-related protein (AgRP). Results indicated that α-MSH expression was selectively decreased, while AgRP expression was selectively increased, within specific hypothalamic subregions following repeated binge-like ethanol drinking. To further explore this relationship, we used site-directed drug delivery techniques to agonize or antagonize MCRs within the lateral hypothalamus (LH). We found that the nonselective MCR agonist melanotan-II (MTII) blunted, while the nonselective MCR antagonist AgRP augmented, binge-like ethanol consumption when delivered into the LH. As these effects were region-specific, the present results suggest that a more thorough understanding of the MC neurocircuitry within the hypothalamus will help provide novel insight into the mechanisms that modulate excessive binge-like ethanol intake and may help uncover new therapeutic targets aimed at treating alcohol abuse disorders.

The present report examined how binge-like ethanol drinking impacts key peptides within the central melanocortin (MC) system. Results showed decreased α-MSH expression and increased agouti-related protein (AgRP) expression within specific hypothalamic sub-regions following repeated binge-like ethanol drinking in male C57BL/6J mice. Consistently, a non-selective MCR agonist (MTII) blunted, while a non-selective MCR antagonist (AgRP) augmented, binge-like ethanol consumption when delivered into the lateral hypothalamus. The present results show that MC signaling within the hypothalamus modulates binge-like ethanol drinking in mice.

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