α5GABAA subunit-containing receptors and sweetened alcohol cue-induced reinstatement and active sweetened alcohol self-administration in male rats

  • Cassie M. Chandler
  • Jaren Reeves-Darby
  • Sherman A. Jones
  • J. Abigail McDonald
  • Guanguan Li
  • Md T. Rahman
  • James M. Cook
  • Donna M. Platt
Original Investigation



GABAA receptors containing the α5 subunit (i.e., α5GABAA receptors) appear to be critically involved in the reinforcing and subjective effects of alcohol. Their role in alcohol relapse remains unknown.


Pharmacological approaches were used to probe the role of α5GABAA receptors in alcohol seeking induced by re-exposure to a sweetened alcohol-paired cue, as well as in alcohol + sucrose vs. sucrose self-administration.


For reinstatement studies, rats were trained to self-administer alcohol under a fixed-ratio schedule in which responding was maintained by alcohol + sucrose deliveries and an alcohol-paired stimulus. Sweetened alcohol seeking was extinguished by eliminating solution deliveries and the sweetened alcohol-paired stimulus. During reinstatement tests, animals received pretreatments of an α5GABAA inverse agonist (L-655,708) or an agonist (QH-ii-066) prior to sessions in which presentation of the sweetened alcohol-paired stimulus was restored, but no solution was delivered. For self-administration studies, rats were trained to self-administer alcohol + sucrose or sucrose under a fixed-ratio schedule. Once stable, animals received pretreatments of QH-ii-066, L-655,708, the inverse agonist RY-023, or naltrexone.


L-655,708 attenuated reinstatement of sweetened alcohol seeking by alcohol + sucrose-paired cues; whereas sweetened alcohol-seeking behavior was augmented by QH-ii-066, albeit at different doses in different rats. Both L-655,708 and RY-023 selectively reduced alcohol + sucrose vs. sucrose self-administration. In contrast, naltrexone reduced both alcohol + sucrose and sucrose self-administration; whereas QH-ii-066 enhanced sucrose self-administration only.


α5GABAA receptors play a key role in the modulation of sweetened alcohol cue-induced reinstatement, as well as in alcohol + sucrose but not sucrose self-administration. Inverse agonist activity at α5GABAA receptors may offer a novel strategy for both the reduction of problematic drinking and the prevention of relapse.


Alcohol Ethanol Reinstatement Self-administration GABAA receptors 



We would like to thank Dr. Joyce Besheer (UNC-Chapel Hill) for invaluable advice regarding alcohol self-administration in rats; Dr. Kevin Freeman (UMMC) for use of his operant conditioning chambers, and Dr. Sally Huskinson for her Med State programming expertise. We also would like to thank the Shimadzu Analytical Laboratory of Southeastern Wisconsin.

Compliance with ethical standards

All animals were maintained and experiments were conducted in accordance with the University of Mississippi Medical Center’s Institutional Animal Care and Use Committee and were in accordance with the National Research Council’s Guide for Care and Use of Laboratory Animals (eighth edition, 2011).

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Graduate Program in NeuroscienceUniversity of Mississippi Medical CenterJacksonUSA
  2. 2.Department of Psychiatry & Human BehaviorUniversity of Mississippi Medical CenterJacksonUSA
  3. 3.Department of Chemistry & BiochemistryUniversity of Wisconsin-MilwaukeeMilwaukeeUSA

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