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 journalArticle

37 Scopus citations

Abstract

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
Volume37
Issue number4
DOIs
StatePublished - Jan 25 2017

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Smith, A. C. W., Scofield, M. D., Heinsbroek, J. A., Gipson-Reichardt, C., Neuhofer, D., Roberts-Wolfe, D. J., Spencer, S., Garcia-Keller, C., Stankeviciute, N. M., Smith, R. J., Allen, N. P., Lorang, M. R., Griffin, W. C., Boger, H. A., & Kalivas, P. W. (2017). Accumbens nNOS interneurons regulate cocaine relapse. Journal of Neuroscience, 37(4), 742-756. https://doi.org/10.1523/JNEUROSCI.2673-16.2016