The Role of the Melanocortin System in Binge-Like Ethanol Consumption

Sprow, Gretchen Marie

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March 22, 2019

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Sprow, Gretchen Marie
- Affiliation: College of Arts and Sciences, Department of Psychology and Neuroscience

Abstract

The melanocortin system has a well-established role in modulating feeding behavior and energy homeostasis. Recent data has also indicated that this system modulates neurobiological responses to ethanol. The goal of this dissertation was to explore the role of the melanocortin system in binge-like ethanol intake, a destructive pattern of ethanol consumption that is linked with the development of dependence in the human population. In Chapter 2, the effect of repeated cycles of binge-like ethanol intake on key components of the melanocortin system was measured using immunohistochemical techniques. In agreement with previous literature, it was observed that excessive ethanol intake is associated with a downregulation of an endogenous melanocortin agonist and an upregulation of an endogenous melanocortin antagonist. As the most robust changes were observed in the lateral hypothalamus (LH), Chapter 3 sought to determine whether site-directed pharmacological manipulation of the melanocortin-4 receptor (MC4R), believed to be the most important melanocortin receptor involved in modulating ethanol-related behaviors, in this region would be sufficient to modulate binge-like ethanol intake. To this end, it was shown that intra-LH agonism blunted, while intra-LH antagonism augmented, binge-like ethanol intake. To date, the intracellular signaling mechanisms activated by agonism at the MC4R are not completely understood. In Chapter 4, we sought to determine whether the blunting of ethanol intake induced by intra-LH melanocortin agonism required signaling through the extracellular signal-related kinase (ERK) pathway. Here, it was shown that intra-LH pre-treatment with an inhibitor of this pathway blunted the expected effect of a potent melanocortin agonist on binge-like ethanol intake, suggesting that melanocortin agonism via MC4R in the LH requires ERK signaling. Together, these data indicate that the melanocortin system, in addition to regulating feeding behavior and energy homeostasis, plays an important role in modulating excessive ethanol intake. Given the present data, we hypothesize that the melanocortin system may be an integral component of overlapping neural circuitry that may be involved in modulating neurobiological responses to both natural (food) and drug reinforcers.

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