This a 10-year competitive renewal of a Merit Award that builds upon a total of 25 years of previously funded research. Over this period we have identified the role of glutamate transmission in the nucleus accumbens as critical for behavioral sensitization and the reinstatement of cocaine seeking in an animal model of relapse. Both pre- and postsynaptic cocaine-induced neuroadaptations have been discovered. Recently, the diverse array of cocaine induced changes discovered in our laboratory and by others have been amalgamated into the glutamate homeostasis hypothesis of addiction wherein dysregulation in the balance between synaptic and nonsynaptic glutamate release and uptake is proposed to be critical in the vulnerability to relapse. Supporting this hypothesis, restoring glutamate homeostasis with N-acetylcysteine (NAC) has been shown to produce enduring protection against reinstated cocaine seeking, and appears to normalize many cocaine-induced changes in synaptic plasticity. In the aim #1 of the present proposal we will further characterize the behavioral protection by NAC, evaluating dose-response curves and duration of action after discontinuing NAC. The remaining 3 aims focus on our recent findings that NAC produces an enduring restoration in measures of glutamate homeostasis and metabotropic glutamate receptor (mGluR) dependent neuroplasticity in the nucleus accumbens. Accordingly, aim #2 evaluates the enduring restoration by NAC in the level and function of nonsynaptic glutamate release via the cystine-glutamate exchanger and glial glutamate uptake.
Aim #3 determines if daily NAC restores classic measures of neuroplasticity, including longterm potentiation, longterm depression and dendritic spine morphology. Finally, aim #4 examines the effects of daily NAC on signaling via presynaptic mGluR2/3 and postsynaptic signaling on mGluR5. Moreover, in this aim it will be determined if mGluR agonists and antagonists can promote or inhibit the capacity of daily NAC to normalize glutamate homeostasis and synaptic plasticity in the nucleus accumbens.

Public Health Relevance

Cocaine addiction is associated with impaired neuroplasticity in the prefrontal cortico-striatal brain circuitry that is important for guiding adaptive behavior. The premise of this proposal is that it is possible to repair this corticostriatal deficit and thereby ameliorate the vulnerability to relapse. Accordingly, we propose to characterize the ability of daily N-acetylcysteine treatment to produce enduring protection from the reinstatement of cocaine seeking, and associate this protection with restoring neuroplasticity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003906-29
Application #
8284213
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Frankenheim, Jerry
Project Start
1984-12-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
29
Fiscal Year
2012
Total Cost
$356,536
Indirect Cost
$114,036
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Stankeviciute, Neringa M; Scofield, Michael D; Kalivas, Peter W et al. (2014) Rapid, transient potentiation of dendritic spines in context-induced relapse to cocaine seeking. Addict Biol 19:972-4
McClure, Erin A; Gipson, Cassandra D; Malcolm, Robert J et al. (2014) Potential role of N-acetylcysteine in the management of substance use disorders. CNS Drugs 28:95-106
Gipson, Cassandra D; Kupchik, Yonatan M; Kalivas, Peter W (2014) Rapid, transient synaptic plasticity in addiction. Neuropharmacology 76 Pt B:276-86
Kalivas, Peter W; Gipson, Cassandra D (2014) "Mourning" a lost opportunity. Psychopharmacology (Berl) 231:3921-2
Mahler, Stephen V; Hensley-Simon, Megan; Tahsili-Fahadan, Pouya et al. (2014) Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors. Addict Biol 19:49-60
Shen, Hao-wei; Scofield, Michael D; Boger, Heather et al. (2014) Synaptic glutamate spillover due to impaired glutamate uptake mediates heroin relapse. J Neurosci 34:5649-57
Spencer, Sade; Brown, Robyn M; Quintero, Gabriel C et al. (2014) ?2?-1 signaling in nucleus accumbens is necessary for cocaine-induced relapse. J Neurosci 34:8605-11
Kupchik, Yonatan M; Scofield, Michael D; Rice, Kenner C et al. (2014) Cocaine dysregulates opioid gating of GABA neurotransmission in the ventral pallidum. J Neurosci 34:1057-66
Shen, Hao-wei; Gipson, Cassandra D; Huits, Martijn et al. (2014) Prelimbic cortex and ventral tegmental area modulate synaptic plasticity differentially in nucleus accumbens during cocaine-reinstated drug seeking. Neuropsychopharmacology 39:1169-77
Reissner, Kathryn J; Brown, Robyn M; Spencer, Sade et al. (2014) Chronic administration of the methylxanthine propentofylline impairs reinstatement to cocaine by a GLT-1-dependent mechanism. Neuropsychopharmacology 39:499-506

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