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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.<\/jats:p>","DOI":"10.7554\/elife.47209","type":"journal-article","created":{"date-parts":[[2019,10,9]],"date-time":"2019-10-09T08:00:19Z","timestamp":1570608019000},"source":"Crossref","is-referenced-by-count":54,"title":["Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion"],"prefix":"10.7554","volume":"8","author":[{"given":"Yoki","family":"Nakamura","sequence":"first","affiliation":[{"name":"Cellular Pathobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilyan I","family":"Dryanovski","sequence":"additional","affiliation":[{"name":"Electrophysiology Research Section, Intramural Research Program, National Institute on Drug Abuse, National 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