Pearl Amy J, Maddern Xavier J, Pinares-Garcia Paulo, Ursich Lauren T, Anversa Roberta G, Shesham Arnav, Brown Robyn M, Reed Felicia M, Giardino William J, Lawrence Andrew J, Walker Leigh C
Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia.
Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, 3052, Australia.
Nat Commun. 2025 Mar 15;16(1):2568. doi: 10.1038/s41467-025-57880-w.
Risky drinking rates are rising, particularly in women, yet sex as a biological variable has only recently gained traction. The centrally projecting Edinger-Westphal (EWcp) nucleus has emerged as a key regulator of alcohol consumption. Here we found that EWcp cells reduce binge drinking specifically in female mice. We show this effect is mediated by the ghrelin receptor (GHSR), with EWcp inhibition blocking ghrelin-induced drinking and Ghsr knockdown in EWcp, but not EWcp or ventral tegmental area cells, reducing binge drinking in females, independent of circulating sex hormones. Female mice showed higher EWcp Ghsr expression, and EWcp neurons were more sensitive to ghrelin. Moreover, intra-EWcp delivery of GHSR inverse agonist and antagonist reduced binge drinking, suggesting direct actions of ghrelin. These findings highlight the EWcp as a critical mediator of excessive alcohol consumption via GHSR in female mice, offering insights into the ghrelin system's role in alcohol consumption.
危险饮酒率正在上升，尤其是在女性中，然而性别作为一个生物学变量直到最近才受到关注。向中枢投射的埃丁格-韦斯特法尔核（EWcp）已成为酒精消费的关键调节因子。在这里，我们发现EWcp细胞特异性地减少雌性小鼠的暴饮行为。我们表明，这种作用是由胃饥饿素受体（GHSR）介导的，EWcp抑制可阻断胃饥饿素诱导的饮酒行为，在EWcp中敲低Ghsr，但不在EWcp或腹侧被盖区细胞中敲低，可减少雌性小鼠的暴饮行为，且与循环性激素无关。雌性小鼠的EWcp Ghsr表达较高，并且EWcp神经元对胃饥饿素更敏感。此外，向EWcp内递送GHSR反向激动剂和拮抗剂可减少暴饮行为，这表明胃饥饿素具有直接作用。这些发现突出了EWcp作为雌性小鼠中通过GHSR介导过度饮酒的关键介质，为胃饥饿素系统在酒精消费中的作用提供了见解。
