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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 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 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+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: α5GABA(A) 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 α5GABA(A) receptors may offer a novel strategy for both reduction of problematic drinking and the prevention of relapse.