A relationship between the aldosterone-mineralocorticoid receptor pathway and alcohol drinking: preliminary translational findings across rats, monkeys and humans
Open accessAbstract
Aldosterone regulates electrolyte and fluid homeostasis through binding to the mineralocorticoid receptors (MRs). Previous work provides evidence for a role of aldosterone in alcohol use disorders (AUDs). We tested the hypothesis that high functional activity of the mineralocorticoid endocrine pathway contributes to vulnerability for AUDs. In Study 1, we investigated the relationship between plasma aldosterone levels, ethanol self-administration and the expression of CYP11B2 and MR (NR3C2) genes in the prefrontal cortex area (PFC) and central nucleus of the amygdala (CeA) in monkeys. Aldosterone significantly increased after 6- and 12-month ethanol self-administration. NR3C2 expression in the CeA was negatively correlated to average ethanol intake during the 12 months. In Study 2, we measured Nr3c2 mRNA levels in the PFC and CeA of dependent and nondependent rats and the correlates with ethanol drinking during acute withdrawal. Low Nr3c2 expression levels in the CeA were significantly associated with increased anxiety-like behavior and compulsive-like drinking in dependent rats. In Study 3, the relationship between plasma aldosterone levels, alcohol drinking and craving was investigated in alcohol-dependent patients. Non-abstinent patients had significantly higher aldosterone levels than abstinent patients. Aldosterone levels positively correlated with the number of drinks consumed, craving and anxiety scores. These findings support a relationship between ethanol drinking and the aldosterone/MR pathway in three different species.
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Inhibiting GR-mediated negative feedback on the HPA axis could lead to increased cortisol levels, which could activate mineralocorticoid receptors and modulate alcohol dependence-related behaviors.
“inhibiting other GR-mediated effects such as the negative feedback on the HPA axis could lead to increased cortisol levels, which could in turn, activate mineralocorticoid receptors (Zalachoras et al., 2013) and modulate alcohol dependence-related behaviors (Aoun et al., 2018).”
From Alcohol dependence and withdrawal increase sensitivity of central amygdalar GABAergic synapses to the glucocorticoid receptor antagonist mifepristone in male rats (2022) · cites this paper as Aoun et al., 2018
CUL3 has wide-ranging effects including on ubiquitination and protein degradation, and de novo mutations in CUL3 are associated with rare diseases affecting response to aldosterone, which is affected by smoking and associated with alcohol use.
“CUL3 has wide-ranging effects, including on ubiquination and protein degradation, and de novo mutations in CUL3 are associated with rare diseases affecting response to the mineralocorticoid aldosterone13, which itself is affected by smoking14 and associated with alcohol use15.”
From Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use (2019) · cites this paper as [15]
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- Authors
- Aoun, E. G., Jimenez, V. A., Vendruscolo, L. F., Walter, N. A. R., Barbier, E., Ferrulli, A., Haass-Koffler, C. L., Darakjian, P., Lee, M. R., Addolorato, G., Heilig, M., Hitzemann, R., Koob, G. F., Grant, K. A., & Leggio, L.
- Affiliations
- Brown University (US)
- Oregon National Primate Research Center (US)
- Scripps Research Institute (US)
- Linköping University (SE)
- Oregon Health & Science University (US)
- National Institutes of Health (US)
- Corresponding author
- Leggio, L
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2017-05-02
- Volume
- 23
- Issue
- 6
- Pages
- 1466-1473
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC5668213
- OpenAlex
- W2610713439
- Cited by
- 60
- References
- 55
- Citations by year
- 2026: 8 · 2025: 2 · 2024: 8 · 2023: 12 · 2022: 9 · 2021: 6 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 2
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Psychiatry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, other-oa)
- Funders
- Vetenskapsrådet
- ERAB: The European Foundation for Alcohol Research (EA0619)
- National Institutes of Health (Z99‐AA999999, AA109431, AA08459, AA010760, P51OD011092)
- National Institute on Alcohol Abuse and Alcoholism (R01AA008459, ZIAAA000218, K01AA023867, AA010760, AA000218, AA 109431, U01AA013484, P50AA010760, AA-08459, R37AA008459, T32AA007468, P60AA010760, R24AA019431)
- National Institute of Mental Health (R25MH101076, MH101076)
- National Institute on Drug Abuse (ZIA-AA000218, AA000218)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- aldosterone, mineralocorticoid receptor, alcoholism, ethanol self-administration, alcohol craving, CYP11B2, central amygdala, prefrontal cortex, anxiety-like behavior, compulsive drinking, ethanol withdrawal, species comparison
- MeSH terms
- Preliminary Data, Adult, Alcohol Drinking, Ethanol, Alcoholism, Aldosterone, Amygdala, Animals, Disease Models, Animal, Humans, Macaca mulatta, Male, Mineralocorticoids, Self Administration, Rats, Wistar, Prefrontal Cortex, Receptors, Mineralocorticoid, Cytochrome P-450 CYP11B2, Rats
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