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Extended Amygdala to Ventral Tegmental Area Corticotropin-Releasing Factor Circuit Controls Binge Ethanol Intake

  • Jennifer A. Rinker
    Affiliations
    Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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  • S. Alex Marshall
    Affiliations
    Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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  • Christopher M. Mazzone
    Affiliations
    Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Department of Pharmacology, University of North Carolina at Chapel Hill, , Chapel Hill, North Carolina
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  • Emily G. Lowery-Gionta
    Affiliations
    Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Department of Pharmacology, University of North Carolina at Chapel Hill, , Chapel Hill, North Carolina
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  • Varun Gulati
    Affiliations
    Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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  • Kristen E. Pleil
    Affiliations
    Department of Pharmacology, University of North Carolina at Chapel Hill, , Chapel Hill, North Carolina
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  • Thomas L. Kash
    Affiliations
    Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Department of Pharmacology, University of North Carolina at Chapel Hill, , Chapel Hill, North Carolina
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  • Montserrat Navarro
    Affiliations
    Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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  • Todd E. Thiele
    Correspondence
    Address correspondence to Todd E. Thiele, Ph.D., Department of Psychology, University of North Carolina at Chapel Hill, Davie Hall, CB# 3270, Chapel Hill, NC 27599-3270.
    Affiliations
    Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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      Abstract

      Background

      Corticotropin-releasing factor (CRF) signaling at the CRF1 receptor (CRF1R) in the ventral tegmental area (VTA) can modulate ethanol consumption in rodents. However, the effects of binge-like ethanol drinking on this system have not been thoroughly characterized, and little is known about the role of CRF2R or the CRF neurocircuitry involved.

      Methods

      The effects of binge-like ethanol consumption on the VTA CRF system were assessed following drinking-in-the-dark procedures. Intra-VTA infusions of selective CRF1R and/or CRF2R compounds were employed to assess the contributions of these receptors in modulating binge-like ethanol consumption (n = 89). To determine the potential role of CRF projections from the bed nucleus of the stria terminalis (BNST) to the VTA, CRF neurons in this circuit were chemogenetically inhibited (n = 32). Binge-induced changes in VTA CRF system protein and messenger RNA were also assessed (n = 58).

      Results

      Intra-VTA antagonism of CRF1R and activation of CRF2R resulted in decreased ethanol intake, which was eliminated by simultaneous blockade of both receptors. Chemogenetic inhibition of local CRF neurons in the VTA did not alter binge-like ethanol drinking, but inhibition of VTA-projecting CRF neurons from the BNST significantly reduced intake.

      Conclusions

      We provide novel evidence that 1) blunted binge-like ethanol consumption stemming from CRF1R blockade requires intact CRF2R signaling, and CRF2R activation reduces binge-like drinking; 2) inhibiting VTA-projecting BNST CRF neurons attenuates binge-like drinking; and 3) binge-like ethanol drinking alters protein and messenger RNA associated with the VTA-CRF system. These data suggest that ethanol-induced activation of BNST-to-VTA CRF projections is critical in driving binge-like ethanol intake.

      Keywords

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