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

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit, receiving strong input from the indirect pathway and regulating a variety of functions, including locomotor output and habit formation. We recently showed that it also acts as a gatekeeper of cocaine-induced behavioral plasticity, as inhibition of parvalbumin-positive cells in the GPe (GPe ^PV ) prevents the development of cocaine-induced reward and sensitization. However, the molecular and circuit mechanisms underlying this function are unknown. Here we show that GPe ^PV cells control cocaine reward and sensitization by inhibiting GABAergic neurons in the substantia nigra pars reticulata (SNr ^GABA ), and ultimately, selectively modulating the activity of ventral tegmental area dopamine (VTA ^DA ) cells projecting to the lateral shell of the nucleus accumbens (NAcLat). A major input to GPe ^PV cells is the indirect pathway of the dorsomedial striatum (DMS ^{D 2} ), which receives DAergic innervation from collaterals of VTA ^DA →NAcLat cells, making this a closed-loop circuit. Cocaine likely facilitates reward and sensitization not directly through actions in the GPe, but rather in the upstream DMS, where the cocaine-induced elevation of DA triggers a depression in DMS ^{D 2} cell activity. This cocaine-induced elevation in DA levels can be blocked by inhibition of GPe ^PV cells, closing the loop. Interestingly, the level of GPe ^PV cell activity prior to cocaine administration is correlated with the extent of reward and sensitization that animals experience in response to future administration of cocaine, indicating that GPe ^PV cell activity is a key predictor of future behavioral responses to cocaine. Single nucleus RNA-sequencing of GPe cells indicated that genes encoding voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability are downregulated in GPe ^PV cells following a single cocaine exposure, 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 also impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its potential as a therapeutic to counteract psychostimulant use disorder. Our findings illuminate the molecular and circuit mechanisms by which the GPe orchestrates brain-wide changes in response to cocaine that are required for reward, sensitization, and self-administration behaviors.