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

Yoki Nakamura, Dilyan I. Dryanovski, Yuriko Kimura, Shelley N. Jackson, Amina S. Woods, Yuko Yasui, Shang Yi Tsai, Sachin Patel, Daniel P. Covey, Tsung Ping Su, Carl R. Lupica*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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.

Original languageEnglish (US)
StatePublished - Oct 2019


  • ADP-ribosylation factor 6
  • Cannabinoid
  • Dopamine neuron
  • Endosome
  • Guanine nucleotide exchange factor
  • Microvesicle
  • Presynaptic
  • Synapse

ASJC Scopus subject areas

  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology
  • General Neuroscience


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