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

Affiliation

Graduate Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, 39216, USA. [Email]

Abstract

BACKGROUND : 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.
OBJECTIVE : 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.

Keywords

Alcohol,Ethanol,GABAA receptors,Reinstatement,Self-administration,