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

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Abstract

Rationale

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.

Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Graduate Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, 39216, USA

    Cassie M. Chandler & Donna M. Platt

  2. Department of Psychiatry & Human Behavior, University of Mississippi Medical Center, 2500 North State St., Jackson, MS, 39216, USA

    Jaren Reeves-Darby, Sherman A. Jones, J. Abigail McDonald & Donna M. Platt

  3. Department of Chemistry & Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, USA

    Guanguan Li, Md T. Rahman & James M. Cook

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  1. Cassie M. Chandler
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  2. Jaren Reeves-Darby
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  3. Sherman A. Jones
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  8. Donna M. Platt
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Correspondence to Donna M. Platt.

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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).

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The authors declare that they have no conflict of interest.

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This research was supported by AA016179 (DMP), MH096463 (JMC) and NS076517 (JMC).

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Chandler, C.M., Reeves-Darby, J., Jones, S.A. et al. α5GABAA subunit-containing receptors and sweetened alcohol cue-induced reinstatement and active sweetened alcohol self-administration in male rats. Psychopharmacology 236, 1797–1806 (2019). https://doi.org/10.1007/s00213-018-5163-6

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