α4-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 A Rs) composed of α4, β, and δ subunits mediate GABAergic tonic inhibition and are potential molecular targets in the modulation of behavioural 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 behavioural responses to food-conditioned cues and the behaviour-potentiating effects of cocaine. α4-subunit constitutive knockout 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, into the NAc had no effect on responding when given alone, but reduced cocaine potentiation of responding for conditioned reinforcers in wildtype 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 emphasise the importance of GABAergic signalling within the NAc in mediating cocaine's effects. Significance Statement This manuscript combines genetic and pharmacological interventions to uncover a critical role for α4-containing GABA A receptors in the nucleus accumbens in instrumental responding for conditioned reinforcers and its potentiation by cocaine, behavioural phenomenon thought to contribute to reward-seeking behaviour. These findings represent an important advancement in our understanding of the neural mechanisms underlying the reinforcing effects of conditioned stimuli and the role of the GABAergic system in this process.