2024-08-20 カリフォルニア大学校アーバイン校(UCI)
<関連情報>
- https://news.uci.edu/2024/08/20/uc-irvine-led-team-finds-that-compound-in-rosemary-extract-can-reduce-cocaine-sensitivity/
- https://www.cell.com/neuron/fulltext/S0896-6273(24)00540-3
コカイン誘発行動可塑性の制御を媒介する淡蒼球の分子および回路決定因子 Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity
Guilian Tian,Katrina Bartas,May Hui,…,Jason Aoto,Geoffrey W. Abbott,Kevin T. Beier
Neuron Published:August 16, 2024
DOI:https://doi.org/10.1016/j.neuron.2024.07.018
Graphical abstract
Highlights
- Globus pallidus is part of a 4-node circuit controlling cocaine sensitivity
- KCNQ3 and KCNQ5 expression is reduced following cocaine administration
- Carnosic acid inhibits GPePV cells through activating KCNQ3/5 heteromers
- Carnosic acid reduces cocaine reward, sensitization, and self-administration
Summary
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.
