Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats
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Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-sweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions [i.e., prefrontal cortex, nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST)], whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism.
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Chronic glucocorticoid receptor blockade with mifepristone, administered systemically during alcohol vapor exposure, prevented the escalation of alcohol intake and blocked the increase in progressive-ratio responding for alcohol in dependent animals.
“Consistent with the hypothesis of blunted glucocorticoids in the HPA and sensitized CRF in the CeA, chronic glucocorticoid receptor blockade with mifepristone, when administered systemically during the course of alcohol vapor exposure, prevented the escalation of alcohol intake and blocked the increase in progressive-ratio responding for alcohol in dependent animals (Vendruscolo et al., 2012).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Vendruscolo et al., 2012
Chronic systemic mifepristone during alcohol vapor exposure in rats blocked escalation of drinking during withdrawal.
“Similarly, the chronic administration of mifepristone, a glucocorticoid and progesterone receptor antagonist, when administered systemically in rats during the course of alcohol vapor exposure, blocked the escalation of drinking during withdrawal that developed during dependence induction (Vendruscolo et al., 2012).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Vendruscolo et al., 2012
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., 2012
The lack of difference between protracted withdrawal and dependent rats indicates further neuroadaptations of the GR system during protracted withdrawal, consistent with previously reported increased CeA GR expression.
“indicative of further neuroadaptations of the GR system occuring during protracted withdrawal consistent with the previously reported increase in CeA GR expression (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., 2012
Protracted alcohol abstinence or withdrawal enhance CeA GR expression.
“protracted alcohol abstinence or withdrawal have been shown to enhance CeA GR expression (Vendruscolo et al., 2012) similary suggesting elevated GR signaling.”
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., 2012
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., 2012
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., 2012
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Self-citation
- Authors
- Vendruscolo, L. F., Barbier, E., Schlosburg, J. E., Misra, K. K., Whitfield, T. W., Logrip, M. L., Rivier, C., Repunte-Canonigo, V., Zorrilla, E. P., Sanna, P. P., Heilig, M., & Koob, G. F.
- Affiliations
- Scripps Research Institute (US)
- National Institute on Alcohol Abuse and Alcoholism (US)
- Salk Institute for Biological Studies (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-05-30
- Volume
- 32
- Issue
- 22
- Pages
- 7563-7571
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3375621
- OpenAlex
- W1977137145
- Cited by
- 319
- References
- 81
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 15 · 2023: 19 · 2022: 27 · 2021: 22 · 2020: 22 · 2019: 25 · 2018: 32 · 2017: 30 · 2016: 26 · 2015: 27 · 2014: 31 · 2013: 26 · 2012: 3
- FWCI
- 11.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AA006420)
- National Institute on Alcohol Abuse and Alcoholism (AA012602, AA013191, R01AA017371, AA006420, P50AA006420, F32AA018914, AA017371, R01AA012602, R01AA013191, T32AA007456, P60AA006420)
- National Institute on Drug Abuse (AA006420, DA-004043, R01DA004043)
- National Institute of General Medical Sciences (GM085659, R01GM085659)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- alcoholism, glucocorticoid receptor, mineralocorticoid receptor, hypothalamic-pituitary-adrenal axis, alcohol withdrawal, mifepristone, nucleus accumbens, bed nucleus of the stria terminalis, central amygdala, progressive ratio responding, quinine
- MeSH terms
- Alcohol Drinking, Ethanol, Analysis of Variance, Animals, Brain, Central Nervous System Depressants, Compulsive Behavior, Conditioning, Operant, Hormone Antagonists, Male, Receptors, Glucocorticoid, Reinforcement Schedule, RNA, Messenger, Self Administration, Substance Withdrawal Syndrome, Mifepristone, Up-Regulation, Behavior, Addictive, Rats, Wistar, Receptors, Mineralocorticoid, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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