a4-Containing GABA _A Receptors on DRD2 Neurons of the Nucleus Accumbens Mediate Instrumental Responding for Conditioned Reinforcers and Its Potentiation by Cocaine

Extrasynaptic GABA _A receptors (GABA _ARs) composed of a4, b, and d subunits mediate GABAergic tonic inhibition and are potential molecular targets in the modulation of behavioral responses to natural and drug rewards. These GABA _ARs 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. a4-Subunit constitutive knock-out mice (a4 ^/) showed higher rates of instrumental responding for reward-paired stimuli in a test of conditioned reinforcement (CRf). A similar effect was seen fol-lowing viral knockdown of GABA _AR a4 subunits within the NAc. Local infusion of the a4b d-GABA _AR-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 a4 ^/ mice. Finally, specific deletion of a4-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 a4-GABA _AR-mediated inhibition of DRD2 neurons reduces instrumental responding for a conditioned reinforcer and its po-tentiation by cocaine and emphasize the importance of GABAergic signaling within the NAc in mediating the effects of cocaine.