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.
Highlights
The abuse potential of ketamine limits its clinical application, but the precise mechanism remains largely unclear
The prefrontal cortex (PFC), nucleus accumbens (NAc), CPu, and hippocampus (Hipp), which are critically involved in various stages of the addiction cycle[32], were collected for untargeted lipidomic analysis using liquid chromatography coupled with tandem mass spectrometry (LC/MS–MS)
The detailed lipid alterations are shown in Supplementary Data 1 and Data 2, and the top ten lipids with the most significant elevation in each brain region are listed (Supplementary Fig. 1d). Several lipids, such as phosphatidylcholines (PCs) and PEs, decreased in the CPu in the ketamine group compared with the saline group (Supplementary Data 1), their alterations varied in different brain regions
Summary
The abuse potential of ketamine limits its clinical application, but the precise mechanism remains largely unclear. Endocannabinoid signaling plays a critical role in mediating the psychostimulant and reinforcing properties of ketamine. Mechanistic studies have suggested that several molecules and signaling cascades are involved in the neurochemical mechanisms of ketamine dependence, such as extracellular signal-regulated kinase (ERK), cAMP-responsive element binding protein (CREB), brain-derived neurotrophic factor, and glycogen synthase kinase 3β, as well as changes in membrane receptors[7,8]. Despite these advances, the downstream effects of ketamine have not been fully elucidated. A study showed that PRDM5 may function as a putative transcriptional repressor of the Mgll gene encoding monoacylglycerol lipase (MAGL)[27], and play a role in central nervous system pathophysiology after spinal cord injury[28]
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