title: The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis.
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.
authors.affiliation: 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.) scofield@musc.edu.
authors.forename: M D
authors.initials: MD
authors.lastname: Scofield
authors.affiliation: 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.).
authors.forename: J A
authors.initials: JA
authors.lastname: Heinsbroek
authors.affiliation: 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.).
authors.forename: C D
authors.initials: CD
authors.lastname: Gipson
authors.affiliation: 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.).
authors.forename: Y M
authors.initials: YM
authors.lastname: Kupchik
authors.affiliation: 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.).
authors.forename: S
authors.initials: S
authors.lastname: Spencer
authors.affiliation: 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.).
authors.forename: A C W
authors.initials: AC
authors.lastname: Smith
authors.affiliation: 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.).
authors.forename: D
authors.initials: D
authors.lastname: Roberts-Wolfe
authors.affiliation: 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.).
authors.forename: P W
authors.initials: PW
authors.lastname: Kalivas
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000503:physiopathology* / Q000517:prevention & control; D018698:Glutamic Acid / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D013287:Illicit Drugs / Q000145:classification* / Q000494:pharmacology*; D058990:Molecular Targeted Therapy; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000503:physiopathology*; D058468:Receptors, Ionotropic Glutamate / Q000378:metabolism; D012008:Recurrence; D019966:Substance-Related Disorders / Q000503:physiopathology* / Q000517:prevention & control; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism
chemical_list: D013287:Illicit Drugs; D058468:Receptors, Ionotropic Glutamate; D050496:Vesicular Glutamate Transport Proteins; D018698:Glutamic Acid