Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion
- National Institute on Drug Abuse, National Institutes of Health, United States
- Vanderbilt University Medical Center, United States
- University of Maryland School of Medicine, 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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
National Institute on Drug Abuse (1ZIADA000487-14)
- Carl Lupica
National Institute on Drug Abuse (1ZIADA000206-33)
- Tsung-Ping Su
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Ethics Statement: All animal procedures were conducted in accordance with the principles as indicated by the NIH Guide for the Care and Use of Laboratory Animals. These animal protocols were also reviewed and approved by the NIDA intramural research program Animal Care and Use Committee, which is fully accredited by the Assessment and Accreditation of Laboratory Animal Care (AAALAC) International (approved protocols: 17-CNRB-15, 16-CNRB-128, 16-INB-1, 16-INB-3, 17-INB-5).
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion
eLife 8:e47209.
https://doi.org/10.7554/eLife.47209
