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

26 Citations (Scopus)

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

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Nitric Oxide Synthase Type I
Interneurons
Cocaine
Cues
Recurrence
Metabotropic Glutamate 5 Receptor
Nucleus Accumbens
Glutamic Acid
Matrix Metalloproteinases
Neurons
Pharmaceutical Preparations
Nitric Oxide
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Self Administration
Caspases
Transgenes
Synapses
Substance-Related Disorders
Rodentia
Electrodes

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Smith, A. C. W., Scofield, M. D., Heinsbroek, J. A., Gipson-Reichardt, C., Neuhofer, D., Roberts-Wolfe, D. J., ... Kalivas, P. W. (2017). Accumbens nNOS interneurons regulate cocaine relapse. Journal of Neuroscience, 37(4), 742-756. https://doi.org/10.1523/JNEUROSCI.2673-16.2017

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

In: Journal of Neuroscience, Vol. 37, No. 4, 25.01.2017, p. 742-756.

Research output: Contribution to journalArticle

Smith, ACW, Scofield, MD, Heinsbroek, JA, Gipson-Reichardt, C, Neuhofer, D, Roberts-Wolfe, DJ, Spencer, S, Garcia-Keller, C, Stankeviciute, NM, Smith, RJ, Allen, NP, Lorang, MR, Griffin, WC, Boger, HA & Kalivas, PW 2017, 'Accumbens nNOS interneurons regulate cocaine relapse', Journal of Neuroscience, vol. 37, no. 4, pp. 742-756. https://doi.org/10.1523/JNEUROSCI.2673-16.2017
Smith ACW, Scofield MD, Heinsbroek JA, Gipson-Reichardt C, Neuhofer D, Roberts-Wolfe DJ et al. Accumbens nNOS interneurons regulate cocaine relapse. Journal of Neuroscience. 2017 Jan 25;37(4):742-756. https://doi.org/10.1523/JNEUROSCI.2673-16.2017
Smith, Alexander C.W. ; Scofield, Michael D. ; Heinsbroek, Jasper A. ; Gipson-Reichardt, Cassandra ; Neuhofer, Daniela ; Roberts-Wolfe, Doug J. ; Spencer, Sade ; Garcia-Keller, Constanza ; Stankeviciute, Neringa M. ; Smith, Rachel J. ; Allen, Nicholas P. ; Lorang, Melissa R. ; Griffin, William C. ; Boger, Heather A. ; Kalivas, Peter W. / Accumbens nNOS interneurons regulate cocaine relapse. In: Journal of Neuroscience. 2017 ; Vol. 37, No. 4. pp. 742-756.
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AU - Neuhofer, Daniela

AU - Roberts-Wolfe, Doug J.

AU - Spencer, Sade

AU - Garcia-Keller, Constanza

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AU - Smith, Rachel J.

AU - Allen, Nicholas P.

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