Alcohol consumption preferentially activates a subset of pro-opiomelanocortin (POMC) producing neurons targeting the amygdala

Background: Alcohol abuse is a worldwide public health concern and leads to an estimated 90,000 alcohol-related deaths in the United States annually. Alcohol may promote its euphoric and motivational effects, in part, by activating the endogenous opioid system. Pro-opiomelanocortin (POMC) producing neurons located within the arcuate nucleus (ArcN) of the hypothalamus make up one circuit of the endogenous opioid system, and heavily projects to reward-related brain areas such as the amygdala, nucleus accumbens (NAc) and ventral tegmental area (VTA). POMC producing neurons release β-endorphin and other peptides that target opioid receptors within reward areas to elicit their associated rewarding effects. Here we explore ArcN POMC neuronal activation, as assessed via FosB expression, following alcohol consumption to determine whether activation varied within subsets of ArcN POMC projection neurons targeting different reward-related areas. Methods: Fluorescent retrobeads were used to label ArcN POMC projection neurons targeting the NAc, amygdala and VTA in POMC-cre mice expressing the reporter tdTomato. Animals (n = 57) were then allowed to voluntarily consume alcohol or water using the drinking-in-the-dark (DID) paradigm, and sacrificed for immunohistochemistry to examine FosB expression within ArcN POMC neurons. Results: Female mice displayed escalation of alcohol intake across DID sessions, whereas males did not. A greater percent of ArcN POMC neurons target the amygdala over the NAc and VTA, and alcohol consumption preferentially activated ArcN POMC neurons targeting the amygdala over other areas. Conclusion: These findings highlight a novel aspect alcohol-induced activation of the endogenous opioid system, whereby alcohol activates a specific subpopulation of ArcN POMC producing neurons that project primarily to the amygdala.