title: Accumbens nNOS Interneurons Regulate Cocaine Relapse.
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 NO-sensitive 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.
  
  
  
  Relapse to cocaine use in a rat model is associated with transient increases in synaptic strength at prefrontal cortex synapses in the nucleus accumbens. We demonstrate the sequence of events that mediates synaptic potentiation and reinstated cocaine seeking induced by cocaine-conditioned cues. Activation of prefrontal inputs to the accumbens by cues initiates spillover of synaptic glutamate, which stimulates metabotropic glutamate receptor 5 (mGluR5) on a small population of interneurons (∼1%) expressing neuronal nitric oxide synthase. Stimulating these glutamate receptors increases nitric oxide (NO) production, which stimulates matrix metalloprotease-2 (MMP-2) and MMP-9 activity in the extracellular space. Manipulating the interaction between mGluR5, NO production, or MMP-2 and MMP-9 pharmacologically or genetically is sufficient to recapitulate transient synaptic potentiation and reinstate cocaine seeking.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Alexander C W
authors.identifier: 0000-0001-7724-6234
authors.initials: ACW
authors.lastname: Smith
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Scofield
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Jasper A
authors.identifier: 0000-0003-4641-6899
authors.initials: JA
authors.lastname: Heinsbroek
authors.affiliation: Department of Psychology, Arizona State University, Tempe, Arizona 85287.
authors.forename: Cassandra D
authors.initials: CD
authors.lastname: Gipson
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Daniela
authors.initials: D
authors.lastname: Neuhofer
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Roberts-Wolfe
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Sade
authors.identifier: 0000-0001-8663-9056
authors.initials: S
authors.lastname: Spencer
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Constanza
authors.initials: C
authors.lastname: Garcia-Keller
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Neringa M
authors.initials: NM
authors.lastname: Stankeviciute
authors.affiliation: Department of Psychology, Institute for Neuroscience, Texas A&M University, College Station, Texas 77843, and.
authors.forename: Rachel J
authors.identifier: 0000-0002-5212-561X
authors.initials: RJ
authors.lastname: Smith
authors.affiliation: Department of Biology, College of Charleston, Charleston, South Carolina 29401.
authors.forename: Nicholas P
authors.identifier: 0000-0002-4015-0885
authors.initials: NP
authors.lastname: Allen
authors.affiliation: Department of Biology, College of Charleston, Charleston, South Carolina 29401.
authors.forename: Melissa R
authors.identifier: 0000-0002-7551-3121
authors.initials: MR
authors.lastname: Lorang
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: William C
authors.identifier: 0000-0002-9896-5905
authors.initials: WC
authors.lastname: Griffin
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Boger
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425, kalivasp@musc.edu.
authors.forename: Peter W
authors.identifier: 0000-0001-9487-0119
authors.initials: PW
authors.lastname: Kalivas
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012008:Recurrence; D012646:Self Administration
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D003042:Cocaine
keywords: MMP; cocaine; glutamate; metabotropic glutamate receptor; nitric oxide; relapse