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

Abstract

Rationale: GABA A receptors containing the α5 subunit (i.e., α5GABA A ) 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 α5GABA A receptors in alcohol seeking induced by re-exposure to an 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 fixedratio schedule in which responding was maintained by alcohol+sucrose deliveries and an alcoholpaired stimulus. Sweetened alcohol seeking was extinguished by eliminating solution deliveries and the sweetened alcohol-paired stimulus. During reinstatement tests, animals received pretreatments of an α5GABA A 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+sucrosepaired 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.

Changes in the elimination and resurgence of alcohol-maintained behavior in rats and the effects of naltrexone.

“…In Experiment 2, it was demonstrated that naltrexone facilitated the elimination of alcoholmaintained behavior when used in conjunction with alternative non-alcohol reinforcers. These results are consistent with previous demonstrations that naltrexone can reduce alcohol-maintained behavior while not significantly decreasing sucrose-maintained behavior (e.g., Chandler et al, 2019) and with its use as an FDA-approved pharmacotherapy for AUD. That this difference was only observed in the first Phase 2 session followed by the rapid elimination of alcohol-maintained behavior in all rats regardless of presession treatment, may be due to the reinforcement parameters used in this experiment.…”

“…The results of Experiment 2 are in line with those of previous experiments in which it was demonstrated that naltrexone can suppress alcohol-maintained behavior and mitigate its relapse (Chandler et al, 2019; Czachowski & Delory, 2009; Lê et al, 1999; Williams & Schimmel, 2008). These results also extend the resurgence literature by further demonstrating that resurgence can be affected by the presession delivery of drugs (Pyszczynski & Shahan, 2014; Quick et al, 2011).…”

“…Naltrexone facilitated the elimination of alcohol-maintained behavior in Phase 2, and why this occurred warrants some consideration. Naltrexone has been demonstrated to selectively reduce the consumption of alcohol compared to other nonalcohol reinforcers such as sucrose (e.g., Chandler et al, 2019). This is, in part, thought to be a result of naltrexone selectively reducing the reinforcing properties of alcohol.…”

“…To evaluate the utility of adjunctive pharmacotherapies to enhance patient outcomes after behavioral therapy, the effects of naltrexone on the elimination and resurgence of alcohol-maintained behavior were assessed. Naltrexone was selected because it has been demonstrated in preclinical studies to reduce the consumption of alcohol (e.g., Chandler et al, 2019), mitigate the reinstatement of alcohol-maintained behavior (e.g., Williams & Schimmel, 2008), and it is FDA-approved for the treatment of AUD.…”

“…One obvious pharmacotherapy to investigate in this role is naltrexone, a μ-opioid antagonist approved by the Food and Drug Administration (FDA) for the treatment of AUD. Naltrexone has been demonstrated to reduce the consumption of alcohol and mitigate relapse to alcohol seeking in preclinical studies (Chandler et al, 2019; Czachowski & Delory, 2009; Lê et al, 1999; Williams & Schimmel, 2008) and in clinical populations (Jonas et al, 2014; Leeman, Bogart, Fucito, & Boettiger, 2014; McLellan et al, 2000; O’Malley et al, 2015; Oslin et al, 2015). Adjunctive pharmacotherapy has the potential to augment behavioral therapies by building in additional supports to maintain treatment effects in the face of lapses in treatment integrity or in maintaining treatment outcomes after behavioral treatment cessation (Roman, Abraham, & Knudsen, 2011; Silverman, DeFulio, & Sigurdsson, 2012).…”