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Alpha4 subunit-containing GABAA receptors in the accumbens shell contribute to the reinforcing effects of alcohol

Authors

  • Mridula Rewal,

    1. Ernest Gallo Clinic and Research Center, University of California at San Francisco, Emeryville, CA, USA
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  • Rachel Donahue,

    1. Ernest Gallo Clinic and Research Center, University of California at San Francisco, Emeryville, CA, USA
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  • T. Michael Gill,

    1. Ernest Gallo Clinic and Research Center, University of California at San Francisco, Emeryville, CA, USA
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  • Hong Nie,

    1. Ernest Gallo Clinic and Research Center, University of California at San Francisco, Emeryville, CA, USA
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  • Dorit Ron,

    1. Ernest Gallo Clinic and Research Center, University of California at San Francisco, Emeryville, CA, USA
    2. Department of Neurology, University of California at San Francisco, San Francisco, CA, USA
    3. Wheeler Center for the Neurobiology of Addiction, University of California at San Francisco, San Francisco, CA, USA
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  • Patricia H. Janak

    Corresponding author
    1. Ernest Gallo Clinic and Research Center, University of California at San Francisco, Emeryville, CA, USA
    2. Department of Neurology, University of California at San Francisco, San Francisco, CA, USA
    3. Wheeler Center for the Neurobiology of Addiction, University of California at San Francisco, San Francisco, CA, USA
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Patricia H. Janak, Ernest Gallo Clinic and Research Center, University of California at San Francisco, 5858 Horton Street Suite 200, Emeryville, CA 94608, USA. E-mail: pjanak@gallo.ucsf.edu

ABSTRACT

The α4βδ gamma-aminobutyric acid A receptor (GABAAR) has been proposed to mediate the rewarding effects of low-to-moderate concentrations of alcohol (ethanol) that approximate those achieved by social drinking. If this is true, then this receptor should be necessary for the reinforcing effects of ethanol as assessed in an instrumental self-administration procedure in which rats are trained to lever press for oral ethanol. We used viral-mediated RNA interference to transiently reduce expression of the α4 GABAAR subunit in the shell region of the nucleus accumbens (NAc). We found that responding for ethanol was significantly reduced after α4 reductions in the NAc shell, but not NAc core. This reduction was specific to ethanol, as responding for sucrose was not altered. The presence of ethanol was also required as unreinforced responding for ethanol in subjects previously trained to respond for ethanol (i.e. responding during an extinction test) was not altered. In addition, responding during reinforced sessions was not altered during the initial 5 minutes of the session, but decreased after 5 minutes, following multiple reinforced responses. Together, these findings indicate that the α4 GABAAR subunit in the NAc shell is necessary for the instrumental reinforcing effects of oral ethanol, further supporting a role for α4-containing GABAARs in the rewarding/reinforcing effects of ethanol. Possible pharmacological and non-pharmacological explanations for these effects are considered.

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