Edinger-Westphal ghrelin receptor signalling regulates binge alcohol consumption in a sex specific manner

Background Rates of risky drinking are continuing to rise, particularly in women, yet sex as a biological variable has been largely ignored. An emerging yet understudied potential component of this circuitry is the central projecting Edinger-Westphal (EWcp), which is made up of two prominent, but distinct cell populations expressing either an array of neuropeptides (including cocaine and amphetamine regulated transcript; CART) or vGlut2 (glutamatergic). Methods Here, we use a combination of approaches including genetic, molecular biology, behavioural testing, and electrophysiology to understand how the EWcp contributes to alcohol consumption in female versus male mice. Results Chemogenetic inhibition of EWcp CART cells reduced binge drinking specifically in female, but not male mice. Further, inhibition of EWcp CART cells prevented ghrelin induced drinking, and viral–mediated ghrelin receptor ( Ghsr ) knockdown in the EWcp reduced binge drinking in female, but not male mice. RNAscope revealed Ghsr expression across peptidergic (marked by CART) and glutamatergic populations in the EWcp, with neurons from female mice more sensitive to bath application of ghrelin than male mice. Targeted knockdown of Ghsr from distinct EWcp populations revealed GHSR signalling on peptidergic, but not glutamatergic cells mediate binge drinking in female mice. Finally, both a GHSR inverse agonist and antagonist delivered directly within the EWcp reduced binge drinking in female mice. Conclusions These findings suggest the EWcp is a region mediating excessive alcohol bingeing through GHSR actions on peptidergic cells (CART-expressing) in female mice and expand our understanding of the neural mechanism(s) underpinning how the ghrelin system mediates alcohol consumption.