Abstract
Rationale
Episodic bouts of social stress can precede the initiation, escalation, or relapse to disordered alcohol intake. Social stress may engender neuroadaptations in the hypothalamic-pituitary-adrenal (HPA) axis and in extrahypothalamic stress circuitry to promote the escalation of alcohol intake.
Objectives
We aimed to (1) confirm a pattern of escalated drinking in socially defeated mice and to (2) test drugs that target distinct aspects of the HPA axis and extrahypothalamic neural substrates for their effectiveness in reducing murine, stress-escalated drinking.
Methods
Male C57BL/6J (B6) mice were socially defeated by resident Swiss-derived males for ten consecutive days receiving 30 bites/day. Ten days after the final defeat, cohorts of B6 mice received continuous or intermittent access to 20% EtOH (w/v) and water. After 4 weeks of drinking, mice were injected with weekly, systemic doses of the CRF-R1 antagonist, CP376395; the glucocorticoid receptor antagonist, mifepristone; the 11-beta-hydroxylase inhibitor, metyrapone; or the 5-alpha-reductase inhibitor, finasteride.
Results
Prior to drug treatments, defeated mice reliably consumed more EtOH than non-defeated controls, and mice given alcohol intermittently consumed more EtOH than those with continuous access. CP376395 (17–30 mg/kg) reduced continuous, but not intermittent EtOH intake (g/kg) in socially defeated mice. Mifepristone (100 mg/kg), however, increased drinking by defeated mice with intermittent access to alcohol while reducing drinking during continuous access. When administered finasteride (100 mg/kg) or metyrapone (50 mg/kg), all mice reduced their EtOH intake while increasing their water consumption.
Conclusions
Mice with a history of episodic social defeat stress were selectively sensitive to the effects of CRF-R1 antagonism, suggesting that CRF-R1 may be a potential target for treating alcohol use disorders in individuals who escalate their drinking after exposure to repeated bouts of psychosocial stress. Future studies will clarify how social defeat stress may alter the expression of extrahypothalamic CRF-R1 and glucocorticoid receptors.
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Acknowledgements
The authors would like to thank J. Thomas Sopko for his assistance during manuscript preparation and Tufts University research assistants, Madeline Kuppe, Ariana Nestler, Kyle Aronson, Janine Elya, Tom Fatkin, Amanda Ho, Diana Sapashnik, Madison Steele, Victoria Stoj, Marissa Heyer, Lena Walton, and Meghan Lauzé for their excellent contributions.
Funding
Research reported in this publication was supported by the National Institute on Alcohol Abuse and Alcoholism under award numbers R01AA013983 (K.A.M.), F31AA025827 (E.L.N.), and F31AA021622 (L.S.H.) and by CAPES-Brazil under award number PAJT 88887.096822/2015-00 (L. A-S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Newman, E.L., Albrechet-Souza, L., Andrew, P.M. et al. Persistent escalation of alcohol consumption by mice exposed to brief episodes of social defeat stress: suppression by CRF-R1 antagonism. Psychopharmacology 235, 1807–1820 (2018). https://doi.org/10.1007/s00213-018-4905-9
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DOI: https://doi.org/10.1007/s00213-018-4905-9