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

The globus pallidus external segment (GPe) acts as a gatekeeper of initial cocaine-induced behavioral plasticity. However, the molecular and circuit mechanisms of action by which it does so are unknown. Here we show that parvalbumin-positive cells in the GPe (GPePV) control cocaine reward and sensitization by selectively modulating activity of dopamine (DA) cells projecting to the lateral shell of the nucleus accumbens (NAc). GPePV cells are embedded in a closed-loop circuit controlled by indirect pathway neurons of the dorsomedial striatum (DMSD2), which in part receive DAergic innervation from collaterals of the ventral tegmental DA neurons projecting to the nucleus accumbens lateral shell (VTADA®NAcLat). The GPePV cells control these VTADA®NAcLat cells indirectly via GABAergic neurons in the substantia nigra pars reticulata (SNrGABA). Cocaine modifies activity in each node in the loop, resulting in long-lasting changes in GPePV and VTADA®NAcLat cell activity, as well as DA levels in the DMS. The principal action of cocaine is likely in the DMS, and this cocaine-induced elevation of DA triggers a depression in the inhibition from DMSD2 cells onto GPePV neurons, increasing activity of GPePV cells. Interestingly, the levels of spontaneous activity of GPePV cells is more strongly related to the extent of reward and sensitization that animals experience in response to future administration of cocaine than the other cell types in the loop, indicating that the activity in GPePV cells is a key predictor of future cocaine-induced behavioral responses. Single nucleus RNA-sequencing of GPe cells indicated that voltage-gated potassium channels Kcnq3 and Kcnq5 that control intrinsic excitability are downregulated in GPePV cells following a single cocaine exposure, contributing to the elevation in GPePV cell excitability. Acutely activating the heteromeric KCNQ3/5 channels using the small molecule carnosic acid, a key psychoactive component of rosemary extract, impaired cocaine reward and learning in a volitional cocaine administration task, 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.