Midbrain ghrelin receptor signalling regulates binge drinking in a sex specific manner

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^peptidergic cells reduce binge drinking specifically in female mice. We show this effect is mediated by the ghrelin receptor (GHSR), with EWcp^peptidergic inhibition blocking ghrelin-induced drinking and Ghsr knockdown in EWcp^peptidergic, but not EWcp^{glutamatergic} or ventral tegmental area cells, reducing binge drinking in females, independent of circulating sex hormones. Female mice showed higher EWcp Ghsr expression, and EWcp^peptidergic 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.