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 (GPePV) cells mediate cocaine responses by selectively modulating ventral tegmental area dopamine (VTADA) cells projecting to the dorsomedial striatum (DMS). Interestingly, GPePV 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 GPePV 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 GPePV cell excitability and impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its therapeutic potential to counteract psychostimulant use disorder.

中文翻译：

---

苍白球中的分子和回路决定因素介导可卡因诱导的行为可塑性的控制


外苍白球 （GPe） 是基底神经节回路的核心组成部分，是可卡因诱导的行为可塑性的守门人。然而，该功能背后的分子和电路机制尚不清楚。在这里，我们表明 GPe 小白蛋白阳性 （GPePV） 细胞通过选择性调节投射到背内侧纹状体 （DMS） 的腹侧被盖区多巴胺 （VTADA） 细胞来介导可卡因反应。有趣的是，未接受过可卡因的小鼠的 GPePV 细胞活性与可卡因后的行为反应相关，可有效预测可卡因敏感性。控制可卡因后内源性细胞兴奋性的电压门控钾通道 KCNQ3 和 KCNQ5 的表达下调，导致 GPePV 细胞兴奋性升高。使用小分子鼠尾草酸（迷迭香）提取物的关键精神活性成分）急性激活含有 KCNQ3 和/或 KCNQ5 的通道，降低 GPePV 细胞兴奋性并损害可卡因奖励、致敏和自愿可卡因摄入量，表明其具有抵消精神兴奋剂使用障碍的治疗潜力。