α4-containing GABA_Areceptors on DRD2-neurons of the nucleus accumbens mediate instrumental responding for conditioned reinforcers, and its potentiation by cocaine

Abstract Extrasynaptic GABA A receptors (GABA A Rs) composed of α4, β, and δ subunits mediate GABAergic tonic inhibition and are potential molecular targets in the modulation of behavioral responses to natural and drug rewards. These GABA A Rs are highly expressed within the nucleus accumbens (NAc), where they influence the excitability of the medium spiny neurons. Here, we explore their role in modulating behavioral responses to food-conditioned cues and the behavior-potentiating effects of cocaine. α4-Subunit constitutive knock-out mice (α4 −/− ) showed higher rates of instrumental responding for reward-paired stimuli in a test of conditioned reinforcement (CRf). A similar effect was seen following viral knockdown of GABA A R α4 subunits within the NAc. Local infusion of the α4βδ-GABA A R-preferring agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; Gaboxadol) into the NAc had no effect on responding when given alone but reduced cocaine potentiation of responding for conditioned reinforcers in wild-type, but not α4 −/− mice. Finally, specific deletion of α4-subunits from dopamine D2, but not D1, receptor-expressing neurons (DRD2 and DRD1 neurons), mimicked the phenotype of the constitutive knockout, potentiating CRf responding, and blocking intra-accumbal THIP attenuation of cocaine-potentiated CRf responding. These data demonstrate that α4-GABA A R-mediated inhibition of DRD2 neurons reduces instrumental responding for a conditioned reinforcer and its potentiation by cocaine and emphasize the importance of GABAergic signaling within the NAc in mediating the effects of cocaine.