The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens

Mol Psychiatry. 2015 Nov;20(11):1448-59. doi: 10.1038/mp.2015.104. Epub 2015 Aug 4.


Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Adult
  • Animals
  • Cocaine / pharmacology
  • Cocaine-Related Disorders / genetics*
  • Cocaine-Related Disorders / pathology*
  • Conditioning, Operant / drug effects
  • Dopamine / metabolism*
  • Dopamine Uptake Inhibitors / pharmacology
  • Genetic Predisposition to Disease / genetics*
  • Glutamic Acid / metabolism*
  • Humans
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Neurons / drug effects
  • Neurons / ultrastructure
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Opioid-Related Disorders / genetics
  • Opioid-Related Disorders / pathology
  • Self Administration
  • Signal Transduction / physiology*
  • Synaptic Potentials / drug effects
  • Synaptic Potentials / genetics
  • Vesicular Glutamate Transport Proteins / deficiency
  • Vesicular Glutamate Transport Proteins / genetics*


  • Dopamine Uptake Inhibitors
  • SLC17A8 protein, human
  • Vesicular Glutamate Transport Proteins
  • Glutamic Acid
  • Cocaine
  • Dopamine