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
Spencer, Sade; Garcia-Keller, Constanza; Roberts-Wolfe, Douglas et al. (2017) Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking. Biol Psychiatry 81:616-624
Taniguchi, Makoto; Carreira, Maria B; Cooper, Yonatan A et al. (2017) HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors. Neuron 96:130-144.e6
Bobadilla, Ana-Clara; Garcia-Keller, Constanza; Heinsbroek, Jasper A et al. (2017) Accumbens Mechanisms for Cued Sucrose Seeking. Neuropsychopharmacology 42:2377-2386
Smith, Alexander C W; Scofield, Michael D; Heinsbroek, Jasper A et al. (2017) Accumbens nNOS Interneurons Regulate Cocaine Relapse. J Neurosci 37:742-756
Spencer, Sade; Kalivas, Peter W (2017) Glutamate Transport: A New Bench to Bedside Mechanism for Treating Drug Abuse. Int J Neuropsychopharmacol 20:797-812
Bobadilla, Ana-Clara; Heinsbroek, Jasper A; Gipson, Cassandra D et al. (2017) Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior. Prog Brain Res 235:93-112
Heinsbroek, Jasper A; Neuhofer, Daniela N; Griffin 3rd, William C et al. (2017) Loss of Plasticity in the D2-Accumbens Pallidal Pathway Promotes Cocaine Seeking. J Neurosci 37:757-767
Kupchik, Yonatan M; Kalivas, Peter W (2017) The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think. Neuropsychopharmacology 42:369-370
Spencer, Sade; Scofield, Michael; Kalivas, Peter W (2016) The good and bad news about glutamate in drug addiction. J Psychopharmacol 30:1095-1098
Stefanik, Michael T; Kupchik, Yonatan M; Kalivas, Peter W (2016) Optogenetic inhibition of cortical afferents in the nucleus accumbens simultaneously prevents cue-induced transient synaptic potentiation and cocaine-seeking behavior. Brain Struct Funct 221:1681-9

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