Binge Ethanol-Drinking Potentiates Corticotropin Releasing Factor R1 Receptor Activity in the Ventral Tegmental Area

Authors

  • Dennis R. Sparta,

    1. Ernest Gallo Clinic and Research Center , Department of Neurology, University of California, San Francisco, California
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  • Frederic Woodward Hopf,

    Corresponding author
    • Ernest Gallo Clinic and Research Center , Department of Neurology, University of California, San Francisco, California
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  • Stuart L. Gibb,

    1. Ernest Gallo Clinic and Research Center , Department of Neurology, University of California, San Francisco, California
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  • Saemi L. Cho,

    1. Ernest Gallo Clinic and Research Center , Department of Neurology, University of California, San Francisco, California
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  • Garret D. Stuber,

    1. Ernest Gallo Clinic and Research Center , Department of Neurology, University of California, San Francisco, California
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  • Robert O. Messing,

    1. Ernest Gallo Clinic and Research Center , Department of Neurology, University of California, San Francisco, California
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  • Dorit Ron,

    1. Ernest Gallo Clinic and Research Center , Department of Neurology, University of California, San Francisco, California
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  • Antonello Bonci

    Corresponding author
    1. NIDA Intramural Research Program, Baltimore, Maryland
    2. Solomon H. Snyder Neuroscience Institute, Johns Hopkins School of Medicine, Baltimore, Maryland
    • Ernest Gallo Clinic and Research Center , Department of Neurology, University of California, San Francisco, California
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  • The first two authors contributed equally to this work.

Reprint requests: Frederic Woodward Hopf, PhD, Gallo Research Center, 5858 Horton St, Suite 200, Emeryville, CA 94608; Tel.: 510-985-3892; Fax: 510-985-3101; E-mail: woody@gallo.ucsf.edu

Antonello Bonci, MD, NIDA Intramural Research Program, 251 Bayview Blvd, Baltimore, MD 21224; Tel.: 443-740-2463; Fax: 510-985-3101; E-mail: antonello.bonci@nih.gov

Abstract

Background

Corticotropin releasing factor (CRF) and urocortin play an important role in many stress responses and also can regulate ethanol (EtOH) intake. Adaptations in CRF signaling in the central amygdala promote EtOH consumption after long-term EtOH intake in dependent animals and also after brief periods of binge EtOH intake. Thus, even brief episodes of EtOH consumption can alter the function of the CRF system, allowing CRF to regulate EtOH intake. Here, we examined whether brief binge EtOH consumption leads to CRF receptor adaptations within the ventral tegmental area (VTA), a structure involved in signaling rewarding and aversive events and important in the development and expression of drug and alcohol addiction.

Methods

We utilized a mouse model of binge drinking known as drinking in the dark (DID), where C57BL/6J mice drink approximately 6 g/kg in 4 hours and achieve blood EtOH concentrations of approximately 100 mg/dl, which is equivalent to binge drinking in humans. We used ex vivo whole-cell recordings from putative VTA dopamine (DA) neurons to examine CRF regulation of NMDA receptor (NMDAR) currents. We also examined the impact of CRF receptor antagonist injection in the VTA on binge EtOH intake.

Results

Ex vivo whole-cell recordings from putative VTA DA neurons showed enhanced CRF-mediated potentiation of NMDAR currents in juvenile mice that consumed EtOH in the DID procedure. CRF-induced potentiation of NMDAR currents in EtOH-drinking mice was blocked by administration of CP-154,526 (3 μM), a selective CRF1 receptor antagonist. Furthermore, intra-VTA infusion of CP-154,526 (1 μg) significantly reduced binge EtOH consumption in adult mice. These results were not due to alterations of VTA NMDAR number or function, suggesting that binge drinking may enhance signaling through VTA CRF1 receptors onto NMDARs.

Conclusions

Altered CRF1 receptor-mediated signaling in the VTA promotes binge-like EtOH consumption in mice, which supports the idea that CRF1 receptors may therefore be a promising pharmacological target for reducing binge drinking in humans.

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