1521-0081/68/3/816–871$25.00 http://dx.doi.org/10.1124/pr.116.012484 PHARMACOLOGICAL REVIEWS Pharmacol Rev 68:816–871, July 2016 Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: JEFFREY M. WITKIN 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 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.) Abstract ...................................................................................818 I. Introduction . ..............................................................................818 II. Modeling Addiction and Relapse in the Laboratory Setting . ...............................819 A. What Are We Trying to Model in Experimental Animals? ...............................819 B. Using Animal Models to Understand Constitutive and Transient Adaptations ...........819 Downloaded from C. Motor Sensitization . ..................................................................819 D. Conditioned Place Preference...........................................................821 E. Self-Administration . ..................................................................822 1. Acquisition . ........................................................................823 2. Maintenance........................................................................823 by guest on September 25, 2021 3. Escalation . ........................................................................824 4. Abstinence. ........................................................................824 5. Relapse.............................................................................825 6. Punishment Models.................................................................825 7. Summary. ........................................................................825 III. Nucleus Accumbens: Composition ..........................................................826 A. Medium Spiny Neurons ................................................................826 B. Interneurons . ........................................................................827 1. Acetylcholine Interneurons..........................................................827 2. Somatostatin–, Neuropeptide Y–, and Neuronal Nitric Oxide Synthase–Expressing Interneurons. ................................................828 C. Glial Cells .............................................................................829 D. Extracellular Matrix . ..................................................................830 IV. Nucleus Accumbens: Connectivity ..........................................................831 A. Nucleus Accumbens Core. ............................................................831 1. Glutamatergic Afferents ............................................................832 2. g-Aminobutyric Acidergic Afferents. ................................................832 3. Dopaminergic Afferents . ............................................................833 4. Nucleus Accumbens Core Efferents. ................................................833 B. Nucleus Accumbens Shell . ............................................................834 1. Glutamatergic Afferents ............................................................834 2. Dopaminergic Afferents . ............................................................835 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. Address correspondence to: Dr. Michael D. Scofield, Department of Neuroscience, Medical University of South Carolina, 70 President Street, Charleston, SC 29407. E-mail: [email protected] dx.doi.org/10.1124/pr.116.012484. 816 The Nucleus Accumbens: Mechanisms of Addiction 817 3. Other Afferents . ..................................................................835 4. Efferents of the Nucleus Accumbens Shell . ..........................................835 V. Drug-Induced Plasticity . ..................................................................835 A. Long-Term Synaptic Plasticity..........................................................836 1. Long-Term Depression . ............................................................836 a. Metabotropic glutamate receptor 2/3–dependent long-term depression ............836 b. Endocannabinoid-dependent long-term depression . ...............................837 c. N-methyl-D-aspartic acid–dependent long-term depression ........................838 d. Dopamine and long-term depression . ..........................................839 e. Opioids and long-term depression ................................................839 2. Long-Term Potentiation. ............................................................839 a. N-methyl-D-aspartic–dependent long-term potentiation . .........................839 b. Calcium-permeable a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors . ..................................................................840 c. Silent synapses..................................................................841 3. Afferent– and Medium Spiny Neuron–Specific Synaptic Plasticity. ...................841 a. Afferent-specific synaptic plasticity...............................................841 i. Prefrontal Cortext to the Nucleus Accumbens . ...............................841 ii. Basolateral Amygdala to the Nucleus Accumbens..............................842 iii. Ventral Hippocampus to the Nucleus Accumbens ..............................842 b. Dopamine receptor 1 medium spiny neuron– and dopamine receptor 2 medium spiny neuron–specific changes . ................................................842 B. Short-Term Synaptic Plasticity . ......................................................842 C. Morphologic Plasticity..................................................................843 D. Functional Relevance of Spine Dynamics ...............................................843 VI. Pharmacological Inhibition of Drug Seeking ................................................845 A. a-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptors .......................846 B. N-Methyl-D-Aspartate Receptors. ......................................................846 C. Group I Metabotropic Glutamate Receptors (Metabotropic Glutamate Receptors 1 and 5) . ..................................................................847 D. Group II Metabotropic Glutamate Receptors (Metabotropic Glutamate Receptors 2 and 3) . ..................................................................849 E. Group III Metabotropic Glutamate Receptors (Metabotropic Glutamate Receptor 7)......850 F. Glial Glutamate Release and Uptake . ................................................852 ABBREVIATIONS: ACh, acetylcholine; AGS, activator of G protein; AMN082, N,N9-dibenzhydrylethane-1,2-diamine dihydrochloride; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AMPAR, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AP5, (2R)-amino-5-phosphonovaleric acid; AZD8529, trifluoromethoxy)phenyl]methyl]-3H-isoindol-1-one; BAC, bacterial artificial chromosome; BLA, basolateral amygdala; CAM, cell adhesion molecule; CaMKII, calmodulin-dependent protein kinase II; CB, cannabinoid; CI, Ca2+ impermeable; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; CP, Ca2+ permeable; CPP, conditioned place preference; CR, conditioned response; CREB, cAMP response element binding protein; CS, conditioned stimulus; DNQX, 6,7-dinitroquinoxaline-2,3-dione; DREADD, designer receptor exclusively activated by designer drugs; eCB, endogenous cannabinoid; ECM, extracellular matrix; EPSC, excitatory postsynaptic current; ERK, extracellular signal–regulated kinase; FR, fixed ratio; GLT, glutamate transporter; GluR, glutamate receptor; HSV, herpes simplex virus; IEG, immediate early gene; ILC, infralimbic cortex; JNJ-16259685, 3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone; LTD, long-term depression; LTP, long-term potentiation; LY293558, (3S,4aR,6R,8aR)-6-[2-(1H-tetrazol-5-yl)ethyl]decahydroisoquinoline-3- carboxylic acid; LY341495, 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine; LY379268, (1S,2R,5R,6R)-2-amino-4-oxabicyclo[3.1.0]- hexane-2,6-dicarboxylic acid; LY404039, (2)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid; mAChR, muscarinic acetylcholine receptor; mEPSC, miniature excitatory postsynaptic current; MFZ 10-7, 3-fluoro-5-[2-(6-methyl-2-pyridinyl)ethynyl]benzonitrile hydrochloride; mGluR, metabotropic glutamate receptor; MK-801, [5R,10S]-[+]-5-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine; MMP, matrix metalloproteinase; MMPIP, 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one;