biostudies-literaturePearl AJDepartment of Health | National Health and Medical Research Council (NHMRC)Department of Health | National Health and Medical Research Council2568https://www.ebi.ac.uk/biostudies/studies/S-EPMC11910522biostudies-literatureUnknown16(1)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. MoreNature communicationsMidbrain ghrelin receptor signalling regulates binge drinking in a sex specific manner.PMC1191052220083442002830Reed FMPearl AJPinares-Garcia PGiardino WJLawrence AJAnversa RGShesham ABrown RMMaddern XJUrsich LTWalker LCfalseMidbrain 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. More2025-01-01T00:00:00Z2025 Mar2026-06-01T19:04:48.907Z2025-04-04T03:04:31.408ZS-EPMC119105224008948610.1038/s41467-025-57880-w