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

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 and Xiaobo Cen ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19780-z

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