Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity

Abstract

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit that acts as a gatekeeper of cocaine-induced behavioral plasticity. However, the molecular and circuit mechanisms underlying this function are unknown. Here, we show that GPe parvalbumin-positive (GPe^PV) cells mediate cocaine responses by selectively modulating ventral tegmental area dopamine (VTA^DA) cells projecting to the dorsomedial striatum (DMS). Interestingly, GPe^PV cell activity in cocaine-naive mice is correlated with behavioral responses following cocaine, effectively predicting cocaine sensitivity. Expression of the voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability following cocaine was downregulated, contributing to the elevation in GPe^PV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPe^PV cell excitability and impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its therapeutic potential to counteract psychostimulant use disorder.

Keywords: behavioral vulnerability; carnosic acid; chemogenetics; cocaine; dopamine; drug abuse; globus pallidus; intrinsic excitability; rabies virus; ventral tegmental area; voltage-gated potassium channels.