Regulation of binge-like ethanol intake by arcuate POMC projection neurons

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ABSTRACT The endogenous opioid system is strongly implicated in the rewarding, reinforcing, and motivational effects of ethanol, as evidenced by the established clinical efficacy of the opioid receptor antagonists naltrexone and nalmefene in reducing ethanol intake, relapse propensity, and craving. Animal studies have demonstrated that ethanol activates various opioid peptide-containing circuits within the brain, including regions of the mesocorticolimbic reward circuitry and amygdala. Recently we have generated multiple lines of evidence indicating that ethanol activates a subset of neurons within the arcuate nucleus (ArcN) of the hypothalamus expressing pro-opiomelanocortin (POMC), which gives rise to numerous bioactive neuropeptides including - endorphin. Using patch clamp electrophysiology, we observed that bath application of ethanol (5-40 mM) increases the firing frequency of ~35% of recorded ArcN POMC neurons. Similarly, using FosB immunohistochemistry, we demonstrated that binge-like ethanol intake activates approximately a subset of ArcN POMC neurons, the majority of which synthesize -endorphin vs. -MSH. Retrograde tracing revealed binge- like ethanol intake primarily activates ArcN POMC neurons projecting to the amygdala, with fewer activated neurons projecting to the ventral tegmental area (VTA) or nucleus accumbens (NAc). Surprisingly, chemogenetic modulation of ArcN POMC neurons without subpopulation delineation had no effect on ethanol intake. However, we speculate that these lack of effects were due to the non-specific nature of activation of a number of ArcN POMC neuron containing subcircuits. Baseline sex differences in binge-like ethanol intake were observed, where female mice consumed significantly more ethanol than their male counterparts, and we observed that ER is the primary female sex hormone receptor located on ArcN POMC neurons as compared to ER or progesterone receptors. Together, these observations have led to our overarching hypothesis that ArcN POMC neuron projections to regions of the mesolimbic reward system regulate binge-like ethanol intake in a sex-dependent manner primarily via ER dependent mechanisms. To test this hypothesis, we have formulated the following inter-related yet independent Specific Aims. In Aim 1, we will determine the effects of ethanol on the neurophysiological properties of ArcN POMC projection neurons. In Aim 2, we will determine the effects of chemogenetic modulation of specific ArcN POMC efferent projection neurons on binge-like ethanol intake. Finally, in Aim 3, we will determine the role of ER on POMC neurons in the regulation of binge-like ethanol intake and potential interactions with midbrain dopamine neurons. Together, these studies will elucidate specific opioid circuits and mechanisms regulating binge-like ethanol intake, which will guide the improvement of neuromodulatory and/or pharmacological approaches for the treatment of alcohol use disorders.