Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals
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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.
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Mifepristone decreased alcohol-cued craving and reduced alcohol consumption in non-treatment-seeking AUD subjects.
“In a human laboratory study of non-treatment-seeking subjects with AUD, mifepristone decreased alcoholcued craving in the laboratory and reduced alcohol consumption during the 1-week treatment phase and 1-week post-treatment phase (Vendruscolo et al., 2015).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Vendruscolo et al., 2015
Mifepristone injected directly in the CeA reduces yohimbine-induced reinstatement of ethanol-seeking in non-dependent rats and alcohol drinking in dependent rats.
“Mifepristone injected directly in the CeA reduced yohimbineinduced reinstatement of ethanol-seeking in non-dependent rats (Simms et al., 2012) and alcohol drinking in dependent rats (Vendruscolo et al., 2015).”
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 Vendruscolo et al., 2015
Increased GR activity in the CeA plays a key role in alcohol-dependence associated behaviors.
“increased GR activity in the CeA has been suggested to play a key role in alcohol-dependence associated behaviors (Repunte-Canonigo et al., 2015;Vendruscolo et al., 2015;Vendruscolo et al., 2012).”
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 Vendruscolo et al., 2015
The GR antagonist mifepristone decreases alcohol consumption in dependent rats during acute withdrawal and protracted abstinence.
“The GR antagonist mifepristone decreases alcohol consumption in dependent rats during acute withdrawal and protracted abstinence.”
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 Vendruscolo et al., 2015
Mifepristone is most efficacious in reducing excessive alcohol drinking in animal models of binge-like drinking, heavy drinking, and alcohol dependence.
“mifepristone has been shown to be most efficacious in reducing excessive alcohol drinking in animal models of binge-like drinking, heavy drinking, and alcohol dependence”
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 Vendruscolo et al., 2015
Acute alcohol withdrawal and protracted abstinence in dependent rats are associated with increased GR signaling and changes in GR-mediated transcriptional activity in the rat central nucleus of the amygdala (CeA).
“Acute alcohol withdrawal and protracted abstinence in dependent rats are associated with increased GR signaling and changes in GR-mediated transcriptional activity in the rat central nucleus of the amygdala (CeA).”
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 Vendruscolo et al., 2015
The greater efficacy of mifepristone in dependent rats reflects increased CeA GR function in alcohol dependence and protracted withdrawal.
“This greater efficacy of mifepristone in dependent rats is in line with previous studies likely reflecting increased CeA GR function in alcohol dependence and protracted withdrawal (Vendruscolo et al., 2015).”
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 Vendruscolo et al., 2015
Alcohol dependence is not associated with altered GR expression levels in the amygdala.
“although alcohol dependence is not associated with altered GR expression levels in the amygdala, recently increased fractions of phosphorylated CeA GR indicative of enhanced receptor activity have been reported in alcohol-dependent rats (Vendruscolo et al., 2015).”
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 Vendruscolo et al., 2015
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References 28 · Cited by 218
- Authors
- Vendruscolo, L. F., Estey, D., Goodell, V., Macshane, L. G., Logrip, M. L., Schlosburg, J. E., McGinn, M. A., Zamora-Martinez, E. R., Belanoff, J. K., Hunt, H. J., Sanna, P. P., George, O., Koob, G. F., Edwards, S., & Mason, B. J.
- Affiliations
- Scripps Research Institute (US)
- Louisiana State University Health Sciences Center New Orleans (US)
- Corcept Therapeutics (United States) (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2015-06-29
- Volume
- 125
- Issue
- 8
- Pages
- 3193-3197
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4563748
- OpenAlex
- W1910403263
- Cited by
- 218
- References
- 28
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 23 · 2023: 21 · 2022: 22 · 2021: 23 · 2020: 21 · 2019: 23 · 2018: 27 · 2017: 18 · 2016: 18 · 2015: 2
- FWCI
- 16.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (AA020839, AA006420)
- National Institute on Alcohol Abuse and Alcoholism (AA012602, R01AA020608, R00AA020839, AA023152, AA022977, AA020839, R01AA021667, R01AA023152, AA006420, P50AA006420, AA020608, K99AA020839, R01AA012602, P60AA006420, R01AA022977)
- National Institute on Drug Abuse (AA006420, K99DA037344)
- Topics
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- glucocorticoid receptor antagonism, mifepristone, alcoholism, alcohol seeking, alcohol craving, amygdala, stress, alcohol consumption, pharmacotherapy
- MeSH terms
- Administration, Oral, Adult, Alcohol Drinking, Alcoholism, Animals, Female, Hormone Antagonists, Humans, Male, Receptors, Glucocorticoid, Mifepristone, Rats
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