Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
Program in Mathematical, Computational, and Systems Biology, University of California, Irvine, Irvine, CA, USA.
Neuron. 2024 Oct 23;112(20):3470-3485.e12. doi: 10.1016/j.neuron.2024.07.018. Epub 2024 Aug 16.
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) cells mediate cocaine responses by selectively modulating ventral tegmental area dopamine (VTA) cells projecting to the dorsomedial striatum (DMS). Interestingly, GPe 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 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 cell excitability and impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its therapeutic potential to counteract psychostimulant use disorder.
苍白球外侧部（GPe）是基底神经节回路的一个核心组成部分，作为可卡因诱导行为可塑性的“守门员”。然而，这种功能的分子和回路机制尚不清楚。在这里，我们表明 GPe 钙调蛋白阳性（GPe）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（VTA）细胞来介导可卡因反应。有趣的是，可卡因未处理的小鼠的 GPe 细胞活性与可卡因后的行为反应相关，有效地预测了可卡因的敏感性。电压门控钾通道 KCNQ3 和 KCNQ5 的表达在可卡因后控制细胞内兴奋性，其表达下调，导致 GPe 细胞兴奋性升高。使用小分子迷迭香酸（rosemary extract 的一种主要精神活性成分）急性激活含有 KCNQ3 和/或 KCNQ5 的通道，可降低 GPe 细胞兴奋性，并损害可卡因奖赏、敏化和自愿性可卡因摄入，表明其具有治疗潜力，可对抗精神兴奋剂使用障碍。
