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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 sweet solution without alcohol, 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.

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Fig. 1: Spironolactone decreased binge-like alcohol drinking in mice.
Fig. 2: Spironolactone did not affect motor coordination or spontaneous locomotion in mice.
Fig. 3: Spironolactone decreased operant alcohol self-administration in alcohol-dependent (DEP) and nondependent (NON) rats.
Fig. 4: Difference-in-difference estimates and 95% confidence intervals of self-reported changes in Alcohol Use Disorders Identification Test-Consumption-C (AUDIT-C) scores associated with spironolactone exposure, overall, by baseline AUDIT-C score, and by average daily dose of spironolactone.

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Acknowledgements

The authors would like to thank all staff involved in data collection, management, and support at the National Institutes of Health Intramural Research Program (NIH IRP) and the following joint post-baccalaureate fellows in the NIDA/NIAAA Clinical Psychoneuroendocrinology and Neuropsychopharmacology and NIDA Neurobiology of Addiction Sections: Brandon Blank, Adriana Gregory-Flores, Claire Pince, and Lia Zallar. The authors would also like to thank Dr. Kendall Bryant (NIAAA) for providing administrative support and guidance during the initial development of the human pharmacoepidemiology study. Finally, the authors would like to thank Dr. Gail Seabold (NIDA) for professional proofreading and editing the manuscript.

Funding

This work was supported by the NIH intramural funding ZIA-DA-000635 and ZIA-AA000218 (Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section – PI: LL), ZIA-DA000602–06 (Neurobiology of Addiction Section – PI: GFK), and NIAAA extramural funding (R01-AA023733, U24-AA020794, U01-AA020790, and U10-AA013566). The content of this article is solely the responsibility of the authors and does not necessarily represent the official view of the funding agencies.

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MF and LL conceptualized the study. MF, CTR, VC, MAM, RCNM, BJT, GFK, ACJ, LL, and LFV designed the study and developed the data analysis plan. For the rodent studies, VC, MAM, SKE, EAD, and LAG conducted the experiments and RCNM, BJT, GFK, and LFV provided support. For the pharmacoepidemiology study, CTR managed and analyzed data and DAF and ACJ provided support. MF, CTR, VC, and MAM wrote the first draft of the manuscript and JES, LL, and LFV contributed to the first draft of the manuscript. All authors reviewed, provided feedback, and approved the final manuscript. GFK, ACJ, and LL provided funding for this study.

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Correspondence to Lorenzo Leggio or Leandro F. Vendruscolo.

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Farokhnia, M., Rentsch, C.T., Chuong, V. et al. Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01736-y

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