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, P. W. Kalivas

Research output: Contribution to journalArticlepeer-review

356 Scopus citations


The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goaldirected 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.Anumber of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These druginduced 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.

Original languageEnglish (US)
Pages (from-to)816-871
Number of pages56
JournalPharmacological Reviews
Issue number3
StatePublished - Jul 2016
Externally publishedYes

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2016 by The American Society for Pharmacology and Experimental Therapeutics.


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