Evidence for independent actions of the CRF and ghrelin systems in binge-like alcohol drinking in mice.

Alcohol use disorder (AUD) and binge drinking are highly prevalent public health issues. Both ghrelin and corticotrophin-releasing factor (CRF) drive stress responses and alcohol drinking. Despite evidence of a relationship between the ghrelin and CRF systems, their potential interaction in modulating alcohol drinking is unclear. We tested the effect of a brain-penetrant CRF1 receptor antagonist (R121919) and a peripherally restricted nonselective CRF receptor antagonist (astressin) on plasma ghrelin levels. We also tested effects of R121919 and astressin alone and combined with the growth hormone secretagogue receptor (GHSR; the ghrelin receptor) antagonist JMV2959 and GHSR antagonist/inverse agonist PF-5190457 in a model of binge-like alcohol drinking in male and female C57BL/6 J mice. The intraperitoneal administration of R121919 but not astressin increased plasma ghrelin levels. R121919 but not astressin reduced binge-like alcohol drinking. CRF receptor antagonism had no effect on the ability of GHSR blockers to reduce alcohol drinking. No sex × drug treatment interactions were observed. These findings suggest that while both CRF receptor antagonism and GHSR antagonism reduce alcohol drinking, these two pharmacological approaches may not interact to mediate binge-like alcohol drinking in mice. Additionally, these results provide evidence that GHSR but not peripheral endogenous ghrelin may be key in driving binge-like alcohol drinking.