Background and Purpose Drugs of abuse, including alcohol, increase dopamine in the mesocorticolimbic system via actions on dopamine neurons in the ventral tegmental area (VTA). Increased dopamine transmission can activate inhibitory G protein signalling pathways in VTA dopamine neurons, including those controlled by GABAB and D2 receptors. Members of the R7 subfamily of regulator of G protein signalling (RGS) proteins can regulate inhibitory G protein signalling, but their influence on VTA dopamine neurons is unclear. Here, we investigated the influence of RGS6, an R7 RGS family memberthat has been implicated in the regulation of alcohol consumption in mice, on inhibitory G protein signalling in VTA dopamine neurons. Experimental Approach We used molecular, electrophysiological and genetic approaches to probe the impact of RGS6 on inhibitory G protein signalling in VTA dopamine neurons and on binge‐like alcohol consumption in mice. Key Results RGS6 is expressed in adult mouse VTA dopamine neurons and it modulates inhibitory G protein signalling in a receptor‐dependent manner, tempering D2 receptor‐induced somatodendritic currents and accelerating deactivation of synaptically evoked GABAB receptor‐dependent responses. RGS6−/− mice exhibit diminished binge‐like alcohol consumption, a phenotype replicated in female (but not male) mice lacking RGS6 selectively in VTA dopamine neurons. Conclusions and Implications RGS6 negatively regulates GABAB‐ and D2 receptor‐dependent inhibitory G protein signalling pathways in mouse VTA dopamine neurons and exerts a sex‐dependent positive influence on binge‐like alcohol consumption in adult mice. As such, RGS6 may represent a new diagnostic and/or therapeutic target for alcohol use disorder.

Drug-induced neuroadaptations in the prefrontal cortex (PFC) have been implicated in drug-associated memories that motivate continued drug use. Chronic cocaine exposure increases pyramidal neuron excitability in the prelimbic subregion of the PFC (PL), an adaptation that has been attributed in part to a suppression of inhibitory signalling mediated by the GABA B receptor (GABA B R) and G protein-gated inwardly rectifying K + (GIRK/Kir3) channels. Although reduced GIRK channel activity in PL pyramidal neurons enhances the motor-stimulatory effect of cocaine in mice, the impact on cocaine reward and associated memories remains unclear. Here, we employed Cre-and CRISPR/Cas9-based viral manipulation strategies to evaluate the impact of GIRK channel or GABA B R ablation in PL pyramidal neurons on cocaineinduced conditioned place preference (CPP) and extinction. Neither ablation of GIRK channels nor GABA B R impacted the acquisition of cocaine CPP. GIRK channel ablation in PL pyramidal neurons, however, impaired extinction of cocaine CPP in male but not female mice. Since ablation of GIRK channels but not GABA B R increased PL pyramidal neuron excitability, we used a chemogenetic approach to determine if acute excitation of PL pyramidal neurons impaired the expression of extinction in male mice. While acute chemogenetic excitation of PL pyramidal neurons induced locomotor hyperactivity, it did not impair the extinction of cocaine CPP. Lastly, we found that persistent enhancement of GIRK channel activity in PL pyramidal neurons accelerated the extinction of cocaine CPP. Collectively, our findings show that the strength of GIRK channel activity in PL pyramidal neurons bi-directionally regulates cocaine CPP extinction in male mice.