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Review ArticleReview Article

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

M. D. Scofield, J. A. Heinsbroek, C. D. Gipson, Y. M. Kupchik, S. Spencer, A. C. W. Smith, D. Roberts-Wolfe and P. W. Kalivas
Jeffrey M. Witkin, ASSOCIATE EDITOR
Pharmacological Reviews July 2016, 68 (3) 816-871; DOI: https://doi.org/10.1124/pr.116.012484
M. D. Scofield
Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
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J. A. Heinsbroek
Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
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C. D. Gipson
Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
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Y. M. Kupchik
Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
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S. Spencer
Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
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A. C. W. Smith
Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
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D. Roberts-Wolfe
Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
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P. W. Kalivas
Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
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Jeffrey M. Witkin
Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
Roles: ASSOCIATE EDITOR
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Abstract

The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.

Footnotes

  • This work was supported by grants from the National Institute on Drug Abuse [DA003906, DA012513, DA015369, and DA038700 (P.W.K.), KDA040004A and DA007288 (M.D.S.), R00DAO36569 (C.D.G.), F30DA038893 (D.R.-W.), DA0377220 (S.S.), and DA007288 (A.C.W.S.)], the National Center for Advancing Translational Sciences [TL1TR000061 (D.R.-W.)], the National Institute of General Medical Sciences [T32GM008716 (D.R.-W.)], and by the Burroughs Wellcome Fund Postdoctoral Enrichment Fellowship.

  • dx.doi.org/10.1124/pr.116.012484.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 68 (3)
Pharmacological Reviews
Vol. 68, Issue 3
1 Jul 2016
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Review ArticleReview Article

The Nucleus Accumbens: Mechanisms of Addiction

M. D. Scofield, J. A. Heinsbroek, C. D. Gipson, Y. M. Kupchik, S. Spencer, A. C. W. Smith, D. Roberts-Wolfe and P. W. Kalivas
Pharmacological Reviews July 1, 2016, 68 (3) 816-871; DOI: https://doi.org/10.1124/pr.116.012484

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Review ArticleReview Article

The Nucleus Accumbens: Mechanisms of Addiction

M. D. Scofield, J. A. Heinsbroek, C. D. Gipson, Y. M. Kupchik, S. Spencer, A. C. W. Smith, D. Roberts-Wolfe and P. W. Kalivas
Pharmacological Reviews July 1, 2016, 68 (3) 816-871; DOI: https://doi.org/10.1124/pr.116.012484
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  • Article
    • Abstract
    • I. Introduction
    • II. Modeling Addiction and Relapse in the Laboratory Setting
    • III. Nucleus Accumbens: Composition
    • IV. Nucleus Accumbens: Connectivity
    • V. Drug-Induced Plasticity
    • VI. Pharmacological Inhibition of Drug Seeking
    • VII. Clinical Outcomes of Targeting Glutamatergic Signaling
    • VIII. Future Possibilities for Glutamate in Addiction
    • IX. Concluding Comments
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