Accumbens nNOS interneurons regulate cocaine relapse

Alexander C.W. Smith, Michael D. Scofield, Jasper A. Heinsbroek, Cassandra Gipson-Reichardt, Daniela Neuhofer, Doug J. Roberts-Wolfe, Sade Spencer, Constanza Garcia-Keller, Neringa M. Stankeviciute, Rachel J. Smith, Nicholas P. Allen, Melissa R. Lorang, William C. Griffin, Heather A. Boger, Peter W. Kalivas

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced relapse is correlated with the induction of transient synaptic potentiation (t-SP) at glutamatergic synapses on medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) and requires spillover of glutamate from prefrontal cortical afferents. We used a rodent self-administration/ reinstatement model of relapse to show that cue-induced t-SP and reinstated cocaine seeking result from glutamate spillover, initiating a metabotropic glutamate receptor 5 (mGluR5)-dependent increase in nitric oxide (NO) production. Pharmacological stimulation of mGluR5 in NAcore recapitulated cue-induced reinstatement in the absence of drug-associated cues. Using NOsensitive electrodes, mGluR5 activation by glutamate was shown to stimulate NO production that depended on activation of neuronal nitric oxide synthase (nNOS). nNOS is expressed in ~1% of NAcore neurons. Using a transgene strategy to express and stimulate designer receptors that mimicked mGluR5 signaling through Gq in nNOS interneurons, we recapitulated cue-induced reinstatement in the absence of cues. Conversely, using a transgenic caspase strategy, the intensity of cue-induced reinstatement was correlated with the extent of selective elimination of nNOS interneurons. The induction of t-SP during cued reinstatement depends on activating matrix metalloproteinases (MMPs) and selective chemogenetic stimulation of nNOS interneurons recapitulated MMP activation and t-SP induction (increase in AMPA currents in MSNs). These data demonstrate critical involvement of a sparse population of nNOS-expressing interneurons in cue-induced cocaine seeking, revealing a bottleneck in brain processing of drug-associated cues where therapeutic interventions could be effective in treating drug addiction.

Original languageEnglish (US)
Pages (from-to)742-756
Number of pages15
JournalJournal of Neuroscience
Issue number4
StatePublished - Jan 25 2017


  • Cocaine
  • Glutamate
  • MMP
  • Metabotropic glutamate receptor
  • Nitric oxide
  • Relapse

ASJC Scopus subject areas

  • General Medicine


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