Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion.

@article{Nakamura:2019uq,

title = {Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion.},

author = {Yoki Nakamura and Dilyan I Dryanovski and Yuriko Kimura and Shelley N Jackson and Amina S Woods and Yuko Yasui and Shang-Yi Tsai and Sachin Patel and Daniel P Covey and Tsung-Ping Su and Carl R Lupica},

url = {https://www.ncbi.nlm.nih.gov/pubmed/31596232},

doi = {10.7554/eLife.47209},

issn = {2050-084X (Electronic); 2050-084X (Linking)},

year  = {2019},

date = {2019-10-09},

journal = {Elife},

volume = {8},

address = {Cellular Pathobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States.},

abstract = {Cocaine is an addictive drug that acts in brain reward areas. Recent evidence suggests that cocaine stimulates synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in midbrain, increasing dopamine neuron activity via disinhibition. Although a mechanism for cocaine-stimulated 2-AG synthesis is known, our understanding of 2-AG release is limited. In NG108 cells and mouse midbrain tissue, we find that 2-AG is localized in non-synaptic extracellular vesicles (EVs) that are secreted in the presence of cocaine via interaction with the chaperone protein sigma-1 receptor (Sig-1R). The release of EVs occurs when cocaine causes dissociation of the Sig-1R from ADP-ribosylation factor (ARF6), a G-protein regulating EV trafficking, leading to activation of myosin light chain kinase (MLCK). Blockade of Sig-1R function, or inhibition of ARF6 or MLCK also prevented cocaine-induced EV release and cocaine-stimulated 2-AG-modulation of inhibitory synapses in DA neurons. Our results implicate the Sig-1R-ARF6 complex in control of EV release and demonstrate that cocaine-mediated 2-AG release can occur via EVs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}