mTOR regulates cocaine-induced behavioural sensitization through the SynDIG1-GluA2 interaction in the nucleus accumbens
mTOR regulates cocaine-induced behavioural sensitization through the SynDIG1-GluA2 interaction in the nucleus accumbens
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mTOR 通过伏隔核中 SynDIG1-GluA2 相互作用调节可卡因诱导的行为敏化
DOI：
10.1038/s41401-021-00760-y
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发表时间：
2021-09-14
影响因子：
8.2
通讯作者：
Cen, Xiao-bo
中科院分区：
文献类型：
--
作者：
Li, Hong-chun;Zhang, Jia-mei;Cen, Xiao-bo
行为敏化是响应药物的运动或刻板印象行为的逐步增加。据信这有助于毒品的增强特性，并在停止药物滥用后复发中发挥重要作用。但是，这种行为的基础机制仍然很众所周知。在这项研究中，我们表明在行为敏化对可卡因的表达过程中激活了MTOR信号传导，并用特定的MTOR抑制剂雷帕霉素（NAC）治疗腹膜内或核内核内或核内核内，会减弱可卡因诱导的可卡因诱导的行为敏化。可卡因在可卡因敏化小鼠的NAC中显着修饰的脑脂质谱，并显着升高了磷脂酰肌醇4-磷酸磷酸盐（PIPS）的水平，包括PIP，PIP2和PIP3。可卡因的行为效应是通过NAC内施用LY294002（一种Akt特异性抑制剂）减弱的，这表明PIPS可能会导致对可卡因的MTOR激活。对MTOR信号传导下游效应子的RNA测序分析表明，可卡因显着降低了Syndig1的表达，Syndig1是MTOR信号的已知底物，并降低了GLUA2的表面表达。相比之下，NAC中AAV介导的Syndig1过表达通过促进Syndig1-GluA2相互作用，从而减弱了细胞内GLUA2内在化，从而维持GLUA2表面表达并抑制可卡因诱导的行为。总之，NAC Syndig1可能通过调节GLUA2的突触表达表达在可卡因诱导的行为敏化中起负调节作用。
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.