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

Abstract

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.

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Fig. 1: Repression of mTOR signalling attenuates cocaine-induced behavioural sensitization.
Fig. 2: mTOR signalling in the NAc participates in the behavioural sensitization to cocaine.
Fig. 3: PI3K-AKT pathway in the NAc is involved in behavioural sensitization to cocaine.
Fig. 4: mTOR regulates SynDIG1 expression in the NAc in the cocaine-sensitized mice.
Fig. 5: NAc SynDIG1 is involved in the cocaine-induced behavioural sensitization.
Fig. 6: SynDIG1 overexpression in withdrawal period suppresses the response to cocaine challenge.

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Acknowledgements

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), and “1·3·5 Project for Disciplines of Excellence, West China Hospital, Sichuan University”.

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HCL and JMZ: conception and design, performed the experiments, acquisition of data as well as analysis and interpretation of data, and wrote the manuscript; RX, RC, XMW, YHW, HLZ, LW, XJW, LHJ, BL, YZ, YYC and YPD: acquisition of data as well as analysis and interpretation of immunostaining data; ML, HQZ: conception and design of behavioural experiments; ZY, LB, and JZ: analysis and interpretation of immunofluorescence data; HBW, JWT, YLZ, and XBC: conceived and supervised this research, as well as drafted and revised the article. All authors read and approved the final manuscript.

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Correspondence to Xiao-bo Cen.

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The authors declare no competing interests.

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Li, Hc., Zhang, Jm., Xu, R. et al. mTOR regulates cocaine-induced behavioural sensitization through the SynDIG1–GluA2 interaction in the nucleus accumbens. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00760-y

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Keywords

  • mTOR
  • behavioural sensitization
  • SynDIG1
  • GluA2
  • nucleus accumbens

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