mTOR regulates cocaine-induced behavioural sensitization through the SynDIG1–GluA2 interaction in the nucleus accumbens  

作　　者：Hong-chun Li Jia-mei Zhang Rui Xu Yong-hai Wang Wei Xu Rong Chen Xue-mei Wan Hao-luo Zhang Liang Wang Xiao-jie Wang Lin-hong Jiang Bin Liu Ying Zhao Yuan-yuan Chen Yan-ping Dai Min Li Hua-qin Zhang Zhen Yang Lin Bai Jie Zhang Hong-bo Wang Jing-wei Tian Ying-lan Zhao Xiao-bo Cen 

机构地区：[1]National Chengdu Center for Safety Evaluation of Drugs,State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy,West China Hospital,Sichuan University,Chengdu 610041,China [2]Ministry of Education,Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong,Yantai University,Yantai 264005,China [3]Histology and Imaging Platform,Core Facilities of West China Hospital,Sichuan University,Chengdu 610041,China

出　　处：《Acta Pharmacologica Sinica》2022年第2期295-306,共12页中国药理学报（英文版）

基　　金：This work was partially supported by National Natural Science Foundation of China(Grants 82071494,81871043,81272459);the National Science and Technology Major Project(2018ZX09201017-009,2018ZX09201018-011);“1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University”.

摘　　要：Behavioral sensitization is a progressive increase in locomotor or stereotypic behaviours in response to drugs. It is believed to contribute to the reinforcing properties of drugs and to play an important role in relapse after cessation of drug abuse. However, the mechanism underlying this behaviour remains poorly understood. In this study, we showed that mTOR signaling was activated during the expression of behavioral sensitization to cocaine and that intraperitoneal or intra-nucleus accumbens (NAc) treatment with rapamycin, a specific mTOR inhibitor, attenuated cocaine-induced behavioural sensitization. Cocaine significantly modified brain lipid profiles in the NAc of cocaine-sensitized mice and markedly elevated the levels of phosphatidylinositol-4-monophosphates (PIPs), including PIP, PIP2, and PIP3. The behavioural effect of cocaine was attenuated by intra-NAc administration of LY294002, an AKT-specific inhibitor, suggesting that PIPs may contribute to mTOR activation in response to cocaine. An RNA-sequencing analysis of the downstream effectors of mTOR signalling revealed that cocaine significantly decreased the expression of SynDIG1, a known substrate of mTOR signalling, and decreased the surface expression of GluA2. In contrast, AAV-mediated SynDIG1 overexpression in NAc attenuated intracellular GluA2 internalization by promoting the SynDIG1–GluA2 interaction, thus maintaining GluA2 surface expression and repressing cocaine-induced behaviours. In conclusion, NAc SynDIG1 may play a negative regulatory role in cocaine-induced behavioural sensitization by regulating synaptic surface expression of GluA2.

关 键 词：TOR behavioural sensitization SynDIG1 GluA2 nucleus accumbens 

分 类 号：R965[医药卫生—药理学]