Endocannabinoid signaling regulates the reinforcing and psychostimulant effects of ketamine in mice.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33235205.
- Also identified by DOI 10.1038/s41467-020-19780-z and PMC identifier 7686380.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Arachidonic Acids
- DNA-Binding Proteins
- Endocannabinoids
- Glycerides
- Ketamine
- Monoacylglycerol Lipases
- Signal Transduction
- Transcription Factors