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. 2021 May 1:188:108510.
doi: 10.1016/j.neuropharm.2021.108510. Epub 2021 Feb 26.

Glucocorticoid receptor modulators decrease alcohol self-administration in male rats

M Adrienne McGinn  1 , Brendan J Tunstall  2 , Joel E Schlosburg  3 , Adriana Gregory-Flores  4 , Olivier George  5 , Giordano de Guglielmo  5 , Barbara J Mason  6 , Hazel J Hunt  7 , George F Koob  8 , Leandro F Vendruscolo  8
Affiliations

Glucocorticoid receptor modulators decrease alcohol self-administration in male rats

M Adrienne McGinn et al. Neuropharmacology. .

Abstract

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.

Keywords: Addiction; Alcohol dependence; Alcohol drinking; Alcoholism.

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Figures

Fig. 1.
Fig. 1.
Effects of GR modulators on alcohol self-administration in alcohol-dependent and nondependent male rats. (A) Decrease in alcohol self-administration in nondependent and alcohol-dependent rats 90 min after systemic CORT118335 administration. *p < 0.05, ***p < 0.001, ****p < 0.0001, vs. 0 mg/kg, regardless of group (overall dose effect, two-way repeated-measures ANOVA followed by Holm-Sidak post hoc test); ###p < 0.001, nondependent vs. alcohol-dependent (overall group effect, two-way repeated-measures ANOVA). NON, nondependent (n = 18); DEP, alcohol-dependent (n = 10). (B) Decrease in alcohol self-administration in nondependent and alcohol-dependent rats 90 min after systemic CORT122928 administration. ***p < 0.001, vs. 0 mg/kg, regardless of group (overall dose effect, two-way repeated-measures ANOVA, followed by Holm-Sidak post hoc test); ###p < 0.001, nondependent vs. alcohol-dependent (overall group effect, two-way repeated-measures ANOVA). NON, nondependent (n = 10); DEP, alcohol-dependent (n = 10). (C) Alcohol self-administration did not change in nondependent and alcohol-dependent rats 90 min after systemic CORT108297 administration. ###p < 0.001, nondependent vs. alcohol-dependent (overall group effect, two-way repeated-measures ANOVA). NON, nondependent (n = 8); DEP, alcohol-dependent (n = 8). (D) Decrease in alcohol self-administration in nondependent and alcohol-dependent rats 90 min after systemic CORT125134 administration. **p < 0.01, vs. 0 mg/kg, regardless of group (overall dose effect, two-way repeated-measures ANOVA followed by Holm-Sidak post hoc test); ###p < 0.001, nondependent vs. alcohol-dependent (overall group effect, two-way repeated-measures ANOVA). NON, nondependent (n = 9); DEP, alcohol-dependent (n = 11). Separate cohorts of dependent and nondependent rats were used to test each compound.
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