Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals

Abstract

Alcoholism, or alcohol use disorder, is a major public health concern that is a considerable risk factor for morbidity and disability; therefore, effective treatments are urgently needed. Here, we demonstrated that the glucocorticoid receptor (GR) antagonist mifepristone reduces alcohol intake in alcohol-dependent rats but not in nondependent animals. Both systemic delivery and direct administration into the central nucleus of the amygdala, a critical stress-related brain region, were sufficient to reduce alcohol consumption in dependent animals. We also tested the use of mifepristone in 56 alcohol-dependent human subjects as part of a double-blind clinical and laboratory-based study. Relative to placebo, individuals who received mifepristone (600 mg daily taken orally for 1 week) exhibited a substantial reduction in alcohol-cued craving in the laboratory, and naturalistic measures revealed reduced alcohol consumption during the 1-week treatment phase and 1-week post-treatment phase in mifepristone-treated individuals. Mifepristone was well tolerated and improved liver-function markers. Together, these results support further exploration of GR antagonism via mifepristone as a therapeutic strategy for alcoholism.

Trial registration: ClinicalTrials.gov NCT01548417.

Figures

Figure 2. Mifepristone reduces alcohol-cued craving and drinking in alcoholics while improving liver function.

(A) Visual Analog Scale (VAS) scores of craving severity in response to in vivo alcohol cues. Higher scores indicate greater craving severity. Data represent the estimated marginal mean ± SD. *P < 0.05, mifepristone vs. placebo (linear mixed effects modeling). (B) Total number of alcoholic drinks consumed per week. Data represent the estimated marginal mean ± SEM. *P < 0.05, mifepristone vs. placebo (linear mixed effects modeling). (C) Liver enzymes: GGT, ALT, and AST. Data represent the mean ± SD. Dotplots display individual observations for each condition. *P < 0.05 within-group change from baseline (multivariate analysis of covariance). n = 26 for placebo and n = 28 for mifepristone.

Figure 1. Increased GR function mediates compulsive-like alcohol self-administration in alcohol-dependent rats.

(A) The phosphorylation of GR at SerS232 in the CeA (2-tailed Student’s t test, †P < 0.05 versus nondep), but not BLA, was increased in dependent (dep) rats compared with nondependent (nondep) rats (n = 6/group). No group differences in total GR levels were observed. Representative Western blots for phosphorylated and total GRs in the CeA are indicated. (B) The blockade of GRs with mifepristone injected systemically (n = 11/group) dose-dependently reduced alcohol intake, specifically in dep rats. (C) The GR-specific antagonist CORT113176 decreased alcohol self-administration (n = 7 for dep and n = 9 for nondep), with increased effectiveness in dep rats. (D) The blockade of GRs with mifepristone injected directly into the CeA (n = 5/group) reduced alcohol intake, specifically in dep rats. (B–D) 2-way repeated-measure ANOVA followed by Duncan’s test (*P < 0.05 vs. 0 mg/kg, †P < 0.0001 vs. nondep). The data represent the mean ± SEM of the number of lever presses performed by the rats in 30-minute operant self-administration sessions. Drugs were injected 90 minutes prior to self-administration sessions. Every lever press (fixed-ratio 1 schedule of reinforcement) resulted in the delivery of 0.1 ml of alcohol (10%, wt/vol) or water. Dotplots display individual observations for each condition.