TY - JOUR TI - Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion AU - Nakamura, Yoki AU - Dryanovski, Dilyan I AU - Kimura, Yuriko AU - Jackson, Shelley N AU - Woods, Amina S AU - Yasui, Yuko AU - Tsai, Shang-Yi AU - Patel, Sachin AU - Covey, Daniel P AU - Su, Tsung-Ping AU - Lupica, Carl R A2 - Westbrook, Gary L A2 - Mackie, Ken A2 - Ford, Christopher A2 - Stella, Nephi VL - 8 PY - 2019 DA - 2019/10/09 SP - e47209 C1 - eLife 2019;8:e47209 DO - 10.7554/eLife.47209 UR - https://doi.org/10.7554/eLife.47209 AB - 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. KW - ADP-ribosylation factor 6 KW - cannabinoid KW - dopamine neuron KW - endosome KW - guanine nucleotide exchange factor KW - microvesicle JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -