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Endocannabinoid signaling regulates the reinforcing and psychostimulant effects of ketamine in mice

Author

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  • Wei Xu

    (West China Hospital, Sichuan University)

  • Hongchun Li

    (West China Hospital, Sichuan University)

  • Liang Wang

    (West China Hospital, Sichuan University)

  • Jiamei Zhang

    (West China Hospital, Sichuan University)

  • Chunqi Liu

    (West China Hospital, Sichuan University)

  • Xuemei Wan

    (West China Hospital, Sichuan University)

  • Xiaochong Liu

    (West China Hospital, Sichuan University)

  • Yiming Hu

    (West China Hospital, Sichuan University)

  • Qiyao Fang

    (West China Hospital, Sichuan University)

  • Yuanyuan Xiao

    (West China Hospital, Sichuan University)

  • Qian Bu

    (West China Hospital, Sichuan University)

  • Hongbo Wang

    (Yantai University)

  • Jingwei Tian

    (Yantai University)

  • Yinglan Zhao

    (West China Hospital, Sichuan University)

  • Xiaobo Cen

    (West China Hospital, Sichuan University)

Abstract

The abuse potential of ketamine limits its clinical application, but the precise mechanism remains largely unclear. Here we discovered that ketamine significantly remodels the endocannabinoid-related lipidome and activates 2-arachidonoylglycerol (2-AG) signaling in the dorsal striatum (caudate nucleus and putamen, CPu) of mice. Elevated 2-AG in the CPu is essential for the psychostimulant and reinforcing effects of ketamine, whereas blockade of the cannabinoid CB1 receptor, a predominant 2-AG receptor, attenuates ketamine-induced remodeling of neuronal dendrite structure and neurobehaviors. Ketamine represses the transcription of the monoacylglycerol lipase (MAGL) gene by promoting the expression of PRDM5, a negative transcription factor of the MAGL gene, leading to increased 2-AG production. Genetic overexpression of MAGL or silencing of PRDM5 expression in the CPu robustly reduces 2-AG production and ketamine effects. Collectively, endocannabinoid signaling plays a critical role in mediating the psychostimulant and reinforcing properties of ketamine.

Suggested Citation

  • Wei Xu & Hongchun Li & Liang Wang & Jiamei Zhang & Chunqi Liu & Xuemei Wan & Xiaochong Liu & Yiming Hu & Qiyao Fang & Yuanyuan Xiao & Qian Bu & Hongbo Wang & Jingwei Tian & Yinglan Zhao & Xiaobo Cen, 2020. "Endocannabinoid signaling regulates the reinforcing and psychostimulant effects of ketamine in mice," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19780-z
    DOI: 10.1038/s41467-020-19780-z
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    Cited by:

    1. Radhika Rawat & Elif Tunc-Ozcan & Tammy L. McGuire & Chian-Yu Peng & John A. Kessler, 2022. "Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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