RGS6 negatively regulates inhibitory G protein signaling in VTA dopamine neurons and positively regulates binge-like alcohol consumption in mice.

BACKGROUND AND PURPOSE: Drugs of abuse, including alcohol, increase dopamine (DA) in the mesocorticolimbic system via actions on DA neurons in the ventral tegmental area (VTA). Increased DA transmission can activate inhibitory G protein signaling pathways in VTA DA neurons, including those controlled by GABAB (GABAB R) and D2 DA (D2 R) receptors. Members of the R7 subfamily of Regulator of G protein Signaling (RGS) proteins can regulate inhibitory G protein signaling, but their influence in VTA DA neurons is unclear. Here, we investigated the influence of RGS6, an R7 RGS family member that has been implicated in the regulation of alcohol consumption in mice, on inhibitory G protein signaling VTA DA neurons.

EXPERIMENTAL APPROACH: We used molecular, electrophysiological, and genetic approaches to probe the impact of RGS6 on inhibitory G protein signaling in VTA DA neurons, and on binge-like alcohol consumption, in mice.

KEY RESULTS: RGS6 is expressed in adult mouse VTA DA neurons and it modulates inhibitory G protein signaling in a receptor-dependent manner, tempering D2 R-induced somatodendritic currents and accelerating deactivation of synaptically evoked GABAB R-dependent responses. RGS6-/- mice exhibit diminished binge-like alcohol consumption, a phenotype recapitulated in female (but not male) mice lacking RGS6 selectively in VTA DA neurons.

CONCLUSIONS & IMPLICATIONS: RGS6 negatively regulates GABAB R- and D2 R-dependent inhibitory G protein signaling pathways in mouse VTA DA 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.