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Alcohol use disorder (AUD) is associated with the dysregulation of brain stress and reward systems, including glucocorticoid receptors (GRs). The mixed glucocorticoid/progesterone receptor antagonist mifepristone and selective GR antagonist CORT113176 have been shown to selectively reduce alcohol consumption in alcohol-dependent rats. Mifepristone has also been shown to decrease alcohol consumption and craving for alcohol in humans with AUD. The present study tested the effects of the GR modulators CORT118335, CORT122928, CORT108297, and CORT125134 on alcohol self-administration in nondependent (air-exposed) and alcohol-dependent (alcohol vapor-exposed) adult male rats. Different GR modulators recruit different GR-associated transcriptional cofactors. Thus, we hypothesized that these GR modulators would vary in their effects on alcohol drinking. CORT118335, CORT122928, and CORT125134 significantly reduced alcohol self-administration in both alcohol-dependent and nondependent rats. CORT108297 had no effect on alcohol self-administration in either group. The present results support the potential of GR modulators for the development of treatments for AUD. Future studies that characterize genomic and nongenomic effects of these GR modulators will elucidate potential molecular mechanisms that underlie alcohol drinking in alcohol-dependent and nondependent states.

Ghrelin is a gastric‐derived peptide hormone with demonstrated impact on alcohol intake and craving, but the reverse side of this bidirectional link, that is, the effects of alcohol on the ghrelin system, remains to be fully established. To further characterize this relationship, we examined (1) ghrelin levels via secondary analysis of human laboratory alcohol administration experiments with heavy‐drinking participants; (2) expression of ghrelin, ghrelin receptor, and ghrelin‐O‐acyltransferase (GOAT) genes (GHRL, GHSR, and MBOAT4, respectively) in post‐mortem brain tissue from individuals with alcohol use disorder (AUD) versus controls; (3) ghrelin levels in Ghsr knockout and wild‐type rats following intraperitoneal (i.p.) alcohol administration; (4) effect of alcohol on ghrelin secretion from gastric mucosa cells ex vivo and GOAT enzymatic activity in vitro; and (5) ghrelin levels in rats following i.p. alcohol administration versus a calorically equivalent non‐alcoholic sucrose solution. Acyl‐ and total‐ghrelin levels decreased following acute alcohol administration in humans, but AUD was not associated with changes in central expression of ghrelin system genes in post‐mortem tissue. In rats, alcohol decreased acyl‐ghrelin, but not des‐acyl‐ghrelin, in both Ghsr knockout and wild‐type rats. No dose‐dependent effects of alcohol were observed on acyl‐ghrelin secretion from gastric mucosa cells or on GOAT acylation activity. Lastly, alcohol and sucrose produced distinct effects on ghrelin in rats despite equivalent caloric value. Our findings suggest that alcohol acutely decreases peripheral ghrelin concentrations in vivo, but not in proportion to alcohol's caloric value or through direct interaction with ghrelin‐secreting gastric mucosal cells, the ghrelin receptor, or the GOAT enzyme. [ABSTRACT FROM AUTHOR]