Dissecting the role of mineralocorticoid receptors in binge-like alcohol drinking in mice: Finerenone as a potential pharmacotherapy.

RATIONALE: Alcohol use disorder (AUD) is a serious public health issue, for which only few pharmacological treatments are currently available. The mineralocorticoid receptor (MR) has been investigated as a potential pharmacotherapeutic target for AUD. Treatment with the prototypical MR antagonist spironolactone has been associated with a reduction of alcohol consumption in rodents and humans. However, spironolactone is a nonselective MR antagonist and has additional activity on other systems, such as androgen and progesterone receptors.

OBJECTIVES

The present study investigated the specific role of MR in modulating alcohol drinking. We tested the effect of selective MR antagonists (finerenone, eplerenone, and PF-03882845), spironolactone’s active metabolites with MR antagonism properties (7α-thiomethylspironolactone [7αTMS] and canrenone), selective MR agonists (aldosterone and fludrocortisone), an androgen receptor antagonist (darolutamide), and a progesterone receptor agonist (dydrogesterone) in a drinking-in-the-dark mouse model of binge-like drinking.

RESULTS

We found that finerenone, eplerenone, and PF-03882845 reduced alcohol intake in both male and female mice, whereas 7αTMS, canrenone, aldosterone, fludrocortisone, darolutamide, and dydrogesterone had no effect. Eplerenone and PF-03882845 but not finerenone also reduced the intake of a sweet solution without alcohol, and eplerenone impaired motor coordination.

Conclusions

These results suggest that MRs but not androgen or progesterone receptors are involved in binge-like alcohol drinking, with finerenone as the most selective and effective MR antagonist in reducing alcohol intake. Our findings support the development of clinical trials with finerenone to evaluate its potential therapeutic effects for AUD.