Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies

Abstract

Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a non-alcohol-containing sweet solution, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity-score matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD.

Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals

“…Clinical trials showed that melperone, a dopamine and serotonin receptor antagonist, has inconsistent effects on alcoholic craving 57,58 . Spironolactone, a mineralocorticoid receptor antagonist, reduced alcohol use in both rats and humans in a recent study 59 . Clomethiazole, a GABA receptor antagonist, also showed effect of treatment for alcohol withdrawal syndrome 60 .…”

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals

“…Trichostatin-a, a histone deacetylase inhibitor, showed effects on H3 and H4 acetylation and neuropeptide Y expression in the amygdala, and prevented the development of alcohol withdrawal-related anxiety in rats 54 . Spironolactone, a mineralocorticoid receptor antagonist, reduced alcohol use in both rats and humans in a recent study 55 . Clomethiazole, a GABA receptor antagonist, also showed an effect in treating alcohol withdrawal syndrome 56 .…”

The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission

“…To model alcohol binge-like drinking, rats were trained to self-administer a sweet alcohol (10% v/v ethanol, 3% w/v glucose, 0.1% w/v saccharin) solution and water under a free-choice, fixed ratio 1 (FR1) schedule of reinforcement in standard operant conditioning chambers (28 × 26 × 20 cm; Med Associates) ( 122 , 123 ). Alcohol-dependent rats were trained similarly except that they received unsweet alcohol (10% v/v ethanol) and water ( 54 , 120 ). Each operant response to the alcohol- or water-associated lever was reinforced with the delivery of 0.1 mL of fluid.…”