VOLUME ONE HUNDRED AND THIRTY SEVEN PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE The Molecular Basis of Drug Addiction VOLUME ONE HUNDRED AND THIRTY SEVEN PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE The Molecular Basis of Drug Addiction Edited by SHAFIQUR RAHMAN Department of Pharmaceutical Sciences, South Dakota State University, Brookings, South Dakota, USA AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 125 London Wall, London EC2Y 5AS, UK The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright © 2016 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, 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the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-803786-7 ISSN: 1877-1173 For information on all Academic Press publications visit our website at http://store.elsevier.com/ CONTRIBUTORS Richard L Bell Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA Thomas P Beresford Department of Veterans Affairs Medical Center, Laboratory for Clinical and Translational Research in Psychiatry, Denver, Colorado, USA Department of Psychiatry, School of Medicine, University of Colorado, Denver, Colorado, USA Patrick Chan Department of Pharmacy and Pharmacy Administration, Western University of Health Sciences, College of Pharmacy, Pomona, California, USA Howard J Edenberg Departments of Biochemistry and Molecular Biology and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA Eric A Engleman Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA Sheketha R Hauser Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA Simon N Katner Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA Kabirullah Lutfy Department of Pharmaceutical Sciences,College of Pharmacy, Western University of Health Sciences, Pomona, California, USA William J McBride Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA Jeanette McClintick Departments of Biochemistry and Molecular Biology and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA Bethany S Neal-Beliveau Department of Psychology, Purdue School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA Pamela M Quizon Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA ix x Contributors Shafiqur Rahman Department of Pharmaceutical Sciences, South Dakota State University, Brookings, South Dakota, USA Patrick J Ronan Department of Veterans Affairs Medical Center, Laboratory for Clinical and Translational Research in Psychiatry, Denver, Colorado, USA Research Service, Sioux Falls VA Health Care System, Sioux Falls, South Dakota, USA Department of Psychiatry and Division of Basic Biomedical Sciences, Sanford School of Medicine at the University of South Dakota, Sioux Falls, South Dakota, USA Wei-Lun Sun Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA Karen K Szumlinski Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, California, USA Joachim D Uys Department of Cellular and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina, USA Jacqueline S Womersley Department of Cellular and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina, USA Narin Wongngamnit Department of Veterans Affairs Medical Center, Laboratory for Clinical and Translational Research in Psychiatry, Denver, Colorado, USA Department of Psychiatry, School of Medicine, University of Colorado, Denver, Colorado, USA Substance Abuse Treatment Program, Department of Veterans Affairs, Denver, Colorado, USA Nurulain T Zaveri Astraea Therapeutics, LLC, Mountain View, California, USA Jun Zhu Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA PREFACE Drug addiction is the most complex and costly neuropsychiatric disorder affecting millions of people in the world Recent surveys indicate that approximately 250 million people are illegal drug users which represent ~4% of the global population Acute and chronic exposure to drugs of abuse produces numerous neurobiological effects, but the cellular and molecular processes involved are only partially understood Neuroscientists around the world are searching for clues that underlie the molecular basis of drug addiction While current scientific breakthroughs have increased the understanding on molecular determinants of drug addiction, limitations exist on effective treatment strategies for many forms of drug addiction Thus, there is a need to translate the current knowledge regarding molecular mechanisms of drug addiction derived from neurobiological research into the discovery of new therapeutics This volume,The Molecular Basis of Drug Addiction, consists of eight chapters written by eminent experts in the field The volume covers important aspects of neuroscience research on drug addiction associated with the neurotransmitter receptors, signaling molecules, and relevant mechanisms implicated in drug addiction The chapters in this volume describe some of the latest concepts in emerging and innovative research, discuss new breakthrough findings, define innovative strategies, and target multiple signaling pathways and genes The primary molecular targets discussed in this volume include extracellular signal-regulated kinase, glutamate-associated genes or proteins, S-glutathionylated proteins, cannabinoid receptor mediated signaling pathways, adenylyl cyclase/cyclic adenosine 3,5-monophosphate protein kinase A, neuronal nicotinic receptors, and nociceptin receptors involved in many forms of drug addiction The first chapter presents and discusses the role of the extracellular signal-regulated kinase and its related intracellular signaling pathways in drug-induced neuroadaptive changes that are associated with drug-mediated psychomotor activity, rewarding properties, and relapse of drug-seeking behaviors (Zhu et al.) The second chapter reviews the role of glutamate neurotransmitter receptor system in mediating the development of alcohol dependence The chapter discusses the expression levels of glutamate-associated genes and/or proteins, including metabotropic and ionotropic receptor subunits and glutamate transporters xi xii Preface in a genetic animal model of alcoholism and highlights the changes in glutamate receptors, transporters, enzymes, and scaffolding proteins involving alcohol dependence (Bell etal.) The third chapter presents and highlights the evidence for S-glutathionylation as a redox-sensing mechanism and how this may be involved in the response to drug-induced oxidative stress The function of S-glutathionylated proteins involved in neurotransmission, dendritic spine structure, and drug-induced behavioral outputs are reviewed with specific reference to alcohol, cocaine, and heroin (Uys and Reissner) The fourth chapter provides a comprehensive account of the state of knowledge regarding mechanisms of Cannabis signaling in the brain and the modulation of key brain neurotransmitter systems involved in addiction and psychiatric disorders (Ronan et al.) The fifth chapter reviews the existing literature on the roles of nociception receptors and associated mechanisms in the rewarding and addictive actions of cocaine (Lutfy and Zaveri) The sixth chapter presents recent insights on the rewarding effects of alcohol as they pertain to different brain nicotinic receptor subtypes and associated signaling pathways that contribute to the molecular mechanisms of alcoholism and/or comorbid brain disorders (Rahman etal.) The seventh chapter focuses on and reviews the adenylyl cyclase and cyclic adenosine 3,5-monophosphate/ protein kinase A system as a central player in mediating the acute and chronic effects of opioids in opiate abusers (Chan and Lutfy) The eighth chapter concentrates on Caenorhabditis elegans, a nonvertebrate model, to study the molecular and genetic mechanisms of drug addiction and to identify potential targets for medication development (Engleman et al.) Together, this body of work not only provides a deeper understanding of our current knowledge on specific neurotransmitter systems, functional proteins, signaling molecules, genes, and additional targets for drug addiction, but also indicates complex interactions between drugs of abuse, endogenous neuromodulators, signaling molecules, and the mechanisms underlying the structural and functional plasticity in the brain I hope that the molecular basis of drug addiction research summarized in this volume will generate new ideas on diverse targets and stimulate translational research for further mechanistic understanding and insight into effective strategies for novel therapeutics in the management of drug addiction I would like to thank all the authors for their outstanding contributions to this volume I am very thankful to Dr P Michael Conn, the Editor-in-Chief of the Book Series, for his guidance Finally, I also thank Ms Mary Ann Preface xiii Zimmerman, the Senior Acquisitions Editor and Ms Helene Kabes, Senior Editorial Project Manager of Elsevier, for their assistance and support in bringing this volume together A special thanks to my wife and daughters for their understanding and love SHAFIQUR RAHMAN Editor CHAPTER ONE Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects Wei-Lun Sun, Pamela M Quizon, Jun Zhu1 Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA Corresponding author: e-mail address: zhuj@sccp.sc.edu Contents Introduction ERK Signaling Pathway ERK Signaling and Drug Addiction 3.1 Cocaine 3.2 Amphetamine 3.3 Methamphetamine 3.4 Marijuana 3.5 Nicotine 3.6 Alcohol (Ethanol) Conclusions and Future Directions Acknowledgment References 14 16 18 20 21 23 25 25 Abstract Addiction to psychostimulants has been considered as a chronic psychiatric disorder characterized by craving and compulsive drug seeking and use Over the past two decades, accumulating evidence has demonstrated that repeated drug exposure causes long-lasting neurochemical and cellular changes that result in enduring neuroadaptation in brain circuitry and underlie compulsive drug consumption and relapse Through intercellular signaling cascades, drugs of abuse induce remodeling in the rewarding circuitry that contributes to the neuroplasticity of learning and memory associated with addiction Here, we review the role of the extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase, and its related intracellular signaling pathways in drug-induced neuroadaptive changes that are associated with drug-mediated psychomotor activity, rewarding properties and relapse of drug seeking behaviors We also discuss the neurobiological Progress in Molecular BiologyandTranslational Science, Volume 137 ISSN 1877-1173 http://dx.doi.org/10.1016/bs.pmbts.2015.10.017 © 2016 Elsevier Inc All rights reserved Wei-Lun Sun et al and behavioral effects of pharmacological and genetic interferences with ERK-associated molecular cascades in response to abused substances Understanding the dynamic modulation of ERK signaling in response to drugs may provide novel molecular targets for therapeutic strategies to drug addiction ABBREVIATIONS AC AMPH Amy BDNF BNST Ca2+ CaM CaMK CB1-R CB2-R CPP CPu CREB DA D1-R D2-R ERK Glu HIPP IEG MAPK MEK METH mGluR1/5 MKP-1/3 MSK NAc nAChRs pCREB pERK PFC pGluN2B PKA PKC pMEK PP2A Adenylyl cyclase Amphetamine Amygdala Brain-derived neurotrophic factor Bed nucleus of the striatal terminals Calcium Calcium/calmodulin CaM kinase Cannabinoid receptor Cannabinoid receptor Conditioned place preference Caudate putamen cAMP response element-binding protein Dopamine-regulated phosphoprotein-32 Dopamine D1 receptor Dopamine D2-Receptor Extracellular signal-regulated kinase Glutamate Hippocampus Immediate early gene Mitogen-activated protein kinase MAPK kinase Methamphetamine Metabotropic glutamate 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eLife 2015;4:e06683 90 Johnson BA Progress in the development of topiramate for treating alcohol dependence: from a hypothesis to a proof-of-concept study Alcohol Clin Exp Res 2004;28(8): 1137–1144 91 Bargmann CI Neurobiology of the Caenorhabditis elegans genome Science 1998;282 (5396):2028–2033 92 Anney RJ, Olsson CA, Lotfi-Miri M, Patton GC, Williamson R Nicotine dependence in a prospective population-based study of adolescents: the protective role of a functional tyrosine hydroxylase polymorphism Pharmacogenetics 2004;14(2):73–81 INDEX A AC See Adenylyl cyclase (AC) pathway AC/cAMP/PKA pathway, 205 ACD See Acute acetaldehyde (ACD) acr-15, 236 Acute acetaldehyde (ACD), 22 Acute morphine administration, 209 Addictive phenotype, 88 Adenylyl cyclase (AC) pathway, 4, 98, 151, 204, 205 adenylyl cyclase, 205 protein kinase A, 207 Adolescent smoking patterns, 189 a2-Adrenoreceptors, 212 Agonistic activity, 187 Alcohol, 21, 42, 101, 184 abuse, 184 alcohol use disorder (AUD), 42 alcohol use disorders identification test (AUDIT), 51 blood alcohol concentrations (BACs), 43 collaborative study on the genetics of alcoholism (COGA), 43 dependence, 190 family history negative (FHN), 43 family history positive (FHP), 43 glutamatergic transmission, 50 ionotropic glutamate receptors, role of, 54 multiple PDZ domain protein (Mpdz), 57 role of glutamate in development of, 51 role of mGlu2 receptor in, 43 single nucleotide polymorphisms (SNPs), 43 syndrome, 184 Alcohol use disorder (AUD), 42 heredity, role of, 43 preventable death, cause of, 42 Alcohol withdrawal–associated delirium tremens, 57 Amino acid, 44 glutamate, 44 a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), 45 a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), 97, 164, 215 AMN082, 164 AMPA See a-Amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA) AMPAR:NMDAR ratio, 97 AMPH See Amphetamine (AMPH) Amphetamine (AMPH), 3, 14, 153, 157 pERK level, 14 Amygdala, 163, 211 Animal models, 130, 190 depression-like behavior in, 190 use of, 230 study of human addiction in, 230 Aniracetam, 54 Antagonism, 23 Antiaddictive actions, 158 Antibiotic, beta-lactam, 55 ceftriaxone, 55 Antioxidant enzymes, 88, 109 Apoptosis, 88, 91, 92, 107 ARCOS See Automation of reports and consolidated orders system (ARCOS) b-Arrestin, 211 AT-202, NOPr agonist, 163 AUD See Alcohol use disorder Autism, 233 Automation of reports and consolidated orders system (ARCOS), 204 B Baclofen, 216 BDNF See Brain derived neurotrophic factor (BDNF) Bed nucleus of stria terminalis (BNST), 133, 218 Behavioral sensitization, 154 Beta-endorphin, 161 Bicuculline, administration of, 214 253 254 BNST See Bed nucleus of stria terminalis (BNST) Brain, 47 astrocytic pathology, 56 circuits, 150, 158 glutamatergic synapse, 44, 47 mGlu receptors, 47 neuronal death, 47 neurotoxicity, 56 PSD-95 expression, 56 reduced glutamine synthetase in, 56 Brain derived neurotrophic factor (BDNF), 12, 167, 190 mediated TrkB phosphorylation, 21 neuroplasticity, 167 Buprenorphine, 158 C Caenorhabditis elegans, 231 addiction related targets/systems/ genes in, 229 anandamide receptors, 245 2-arachidonoylglycerol receptors, 245 Bristol (N2) wild-type, 234 cannabinoid receptors, 245 cholinergic neurotransmission, 238 depressant effects on locomotor activity of, 233 drugs of abuse convergent mechanisms of, 238 monoamine neurotransmissionassociated genes, 238 embryonic EtOH exposure in, 245 EtOH-associated behaviors in, 233 EtOH-induced muscle hypercontraction (EHC), 234 genetics/molecular make-up of, 233 model for psychiatric disorders, 233 Na+/K+ ATPase, function of, 234 neuropeptide Y (NPY), receptor homolog of, 234 nicotinic acetylcholine receptor (nAChRs), 235 swsn-9, homolog to, 235 tyrosine hydroxylase (cat-2), mutations in, 233 voltage-sensitive sodium channels, 246 Index Calcium homeostasis, 91 Calphostin C, 208 cAMP-regulated phosphoprotein, 94 cAMP response element-binding protein phosphorylation (pCREB), cAMP responsive element binding (CREB), 191, 209 antisense oligonucleotides, 214 binding protein, 209 gene disruption, 214 opioid effect on, 209 phosphorylation of, 209, 214 Cannabinoid, 125 receptors, 18 types, 125 cannabichromene (CBC), 125 cannabicyclol (CBL), 125 cannabidiol (CBD), 125 cannabielsoin (CBE), 125 cannabigerol (CBG), 125 cannabinodiol (CBND), 125 cannabinol (CBN), 125 cannabitriol (CBT), 125 Cannabis, 124 chemical components, 124 amino acids, 125 esters, 125 fatty acids, 125 flavonoids, 125 glycoproteins, 125 hydrocarbons, 125 ketones, 125 lactones, 125 nitrogenous compounds, 125 noncannabinoid phenols, 125 pigments, 125 proteins, 125 simple alcohols, 125 steroids, 125 sugars, 125 terpenes, 125 vitamins, 125 Catecholamines, synthesis of, 108, 152 cat-2, mutation of, 238 Caudate putamen (CPu), C57BL/6 mice, 154 CB1 receptors, 128 Index CB2 receptors, 129 CDK5 See Cyclin-dependent kinase (CDK5) Cdk5/p35 complex, 100 Cellular redox status, 92 Central nervous system (CNS), 44, 185 Charlotte’s web, 138 Chinese hamster ovary (CHO), 206 CHO See Chinese hamster ovary (CHO) CHRNA6 polymorphisms, 189 Chromatin-remodeling system, 167, 235 conserved switching defective/sucrose nonfermenting (SWI/SNF), 235 Chronic morphine administration, 209 Classical opioid receptors, 205 Clonidine, 212 CNQX See 6-Cyano-7-dinitroquinoxaline-2, 3-dione (CNQX) CNS See Central nervous system Cocaine, 6, 54, 93, 97, 99, 189, 236 addiction, 54, 99, 100, 150, 156 dopamine levels, enhancing of, 150 FDA approved pharmacotherapy for, 150 ionotropic glutamate receptor, expression of, 54 molecular mechanisms of, 158 receptor systems affecting dopamine levels, 150 cholinergic agonists, 150 endocannabinoid, 150 g-amino butyric acid, 150 opioidergic, 150 serotonergic, 150 administration, 100 behavioral sensitization, 6, 154 cessation of, 12 endogenous OFQ/N for addictive actions of, 156 exogenous OFQ/N effects on, 152 GluN2B phosphorylation, locomotor activity, motor-stimulatory action of, 159 NOPr agonist effects against, 157 pERK level, sensitization, 154 treatment, 164 255 Cocaine-induced behavioral sensitization, 164 Cocaine-induced hyperlocomotion 99, 159 Cocaine-induced locomotor sensitization, 157 Cocaine-induced motor stimulation, 154 Cocaine-mediated neuroplasticity, 107 COGA See Collaborative study on the genetics of alcoholism (COGA) Collaborative study on the genetics of alcoholism (COGA), 43 Comorbid psychiatric condition, 190 anxiety, 190 depression, 190 Conditioned place preference (CPP) paradigm, 5, 130, 153, 210, 232 Conjugation, 89 Conserved switching defective/sucrose nonfermenting (SWI/SNF), 235 Corticolimbic glutamatergic neurons, 158 Corticotropin-releasing factor (CRF), 163 Corticotropin releasing hormone (CRH), 163 CPP See Conditioned place preference (CPP) paradigm CPu See Caudate putamen (CPu) CREB See cAMP responsive element binding (CREB) CRF See Corticotropin-releasing factor (CRF) CRH See Corticotropin releasing hormone (CRH) CTAP See D-Phe-Cys-Tyr-D-Trp-ArgThr-Pen-Thr-NH2 (CTAP) Cue-nodrug associations, 164 6-Cyano-7-dinitroquinoxaline-2, 3-dione (CNQX), 212 Cyclic AMP (cAMP)-dependent protein kinase pathway, 94 Cyclin-dependent kinase (CDK5) 94, 167 activation, 97, 100 expression, 100 inhibitor, 100 256 (1-[(3R, 4R)-1-Cyclooctylmethyl-3hydroxymethyl-4-piperidyl]-3ethyl-1, 3-dihydro-2Hbenzimidazol-2-one), 156 Cysteinyl-catechols, 92 Cystine, glutathione synthesis, 47 Cytoplasmic proteins, 89 Cytoskeletal protein, 99 rearrangement, 91 D DA See Dopamine (DA) DAMGO application, 214 DAWN See Drug abuse warning network (DAWN) Deglutathionylation, 89 Dendritic spines, 100 3, 6-Diacetyl ester, 107 Diacylglycerol, 94, 98 6, 7-Dinitroquinoxaline-2, 3-dione, 54 Dizocilpine, 164 DNA, 88 methylation study of, 58 DNA damage, 108 Dopamine (DA), 3, 92, 101, 214 deficient mutants, 236 induced oxidative stress, 92 metabolism, 92 neurotoxin 6-hydroxydopamine, 236 receptors of, 150, 236 dop-1, 236 dop-2, 236 transporter (DAT-1), 150, 159, 236 Dopaminergic neurotransmission 97, 100, 191 Dopaminergic signaling, 92 Dopaminoceptive neurons, 97 Dorsal raphe (DR), 136 Dorsal raphe nucleus (DRN), 210 D-Phe-Cys-Tyr-D-Trp-Arg-Thr-PenThr-NH2 (CTAP), 208 DR See Dorsal raphe (DR) D1R mediated signaling, 94 stimulation, 94 DRN See Dorsal raphe nucleus (DRN) Index Drosophila melanogaster, 232 Drug abuse, 165, 231 alcohol, 231 cocaine, 231 ethanol, 233 methamphetamine, 231 nicotine, 231 signaling pathways, 97 Drug abuse warning network (DAWN), 204 Drug addiction, 3, 92, 94, 190, 230 alcohol addiction, 230 animal models, use of, 230 behavioral changes in, 154 craving, 154 relapse, 154 Caenorhabditis elegans, 231 ethanol (EtOH), 231 invertebrate models for, 232 conditioned place preference (CPP), 232 dopamine neurotransmission, 232 models of, 231 molecular mechanisms of, 232, 233 neurobiology of, 230 nicotine addiction, 230 Drug administration, 164 Drug-induced neurotransmission, 99 Drug-induced plasticity, 100 Drug-seeking behavior, 92, 150, 153 Drugs, hedonic effects of, 155 Dynorphin, 151, 152 E EAA See Excitatory amino acids (EAA) EHC See EtOH-induced muscle hypercontraction Endocannabinoid system, 125 neurogenesis, 125 synaptic plasticity, 125 Endogenous antioxidant, defense mechanisms, 88 Energy metabolism, 91 Enkephalins, 161, 216 ENT See Equilibrative nucleoside transporter (ENT) 257 Index Enzymatic oxidation, 92 Epigenetics, 235 Epilepsy, 89 EPSCs See Excitatory postsynaptic currents (EPSCs) Equilibrative nucleoside transporter (ENT), 137 ERK See Extracellular signal-regulated kinases (ERK) Ethanol (EtOH), 97, 99, 231 abuse, 186 addiction, 94 behavioral effects of, 102 dependent behavior, 189 metabolism increases ROS production, 102 preferring rats, 188 protein S-glutathionylation in response to, 103 ROS productionand behavioral effects of, 102 seeking behavior, 155 self-administration, 52 AMPA receptors, effect on, 54 2-methyl-6-(phenylethynyl)pyridine (MPEP), effect of, 52 NMDA receptors, effect on, 54 (-)-Ethyl (7E)-7-hydroxyimino-1, 7adihydrocyclopropa[b]chromene1a-carboxylate (CPCCOEt), 53 EtOH See Ethanol EtOH-induced muscle hypercontraction (EHC), 234 Excitatory amino acids (EAA), 212 aspartate, 212 glutamate, 212 Excitatory postsynaptic currents (EPSCs), 215 Excitotoxicity, 55 Extracellular accumbal dopamine, 152 Extracellular signal-regulated kinases (ERK), 3, 98 signaling, 4, 5, 210 F Family history negative (FHN), 43 Family history positive (FHP), 43 FHN See Family history negative FHP See Family history positive Forced swim test (FST), 136 FST See Forced swim test (FST) G GABA See g-Aminobutyric acid (GABA) GABAA receptor signaling, 101 GABAB receptors, 101 GABAergic interneurons, 98, 210 GABAergic neurotransmission, 214 GABA signaling, 101 GABA transporter-1 (GAT), 216 Gad1, polymorphisms in, 58 Gad2, polymorphisms in, 58 Gai proteins, 211 Galantamine, 17 g-Aminobutyric acid (GABA), 210 GASP1 See G protein receptor associated sorting protein-1 (GASP1) GAT See GABA transporter-1 (GAT) Gene editing technology, 246 CRISPR, 246 Gene expression, 167 Gene studies collaborative study on the genetics of alcoholism (COGA), 43 European research project on risk-taking behavior in teenagers (IMAGEN), 43 Study of Addiction: Genes and Environment (SAGE), 43 Genetic polymorphisms, 189, 233 Gi/o opioid receptors, 98 Glial cell line-derived neurotrophic factor (GNDF), 12 Glu See Glutamate (Glu) Gluk1, polymorphism in, 57 Glun2a, polymorphism in, 57 Glu-receptor-mediated ERK activity, 22 Glutamate, 44, 45 alcohol dependence, 48 alcohol’s effects on activity of, 48 on extracellular levels of, 48 carriers of, 47 central activity of, 50 258 Glutamate cont dehydrogenase, 56 enzyme activity, 56 expression differences for enzymes, 66 for postsynaptic density, 66 gene expression, 59 for proteins of synapse, differences between P and NP rats, 60 genetic variations, 57 gene set enrichment analysis (GSEA), 57 genome wide association study (GWAS), 57 P300 event-related potential (ERP), 58 theta event-related oscillations (EROs), 58 ionotropic receptors expression differences, 63 Glua1, expression levels of, 63 Glua4, expression levels of, 63 receptor subunit gene differences between P and NP rats, 60 ionotropic receptors of, 47, 54 glia cells, 47 kainate, 47 ligand-gated ion channels, 47 metabolism of, 48 glutamate decarboxylase (GAD), 48 glutamatergic synapse in brain, 44 glutaminase, 48 neurotoxicity, 48 metabotropic receptors, 45, 52 ERK1/2 phosphorylation, 52 expression differences of, 61 receptor (mGluR) Gene (mGlu) expression between P and NP Rats, 60 glutamatergic synapse in brain, 44 2-methyl-6-(phenylethynyl)pyridine (MPEP), 52 mGlu5 antagonist, 52 protein kinase C-epsilon (PKC-epsilon), 52 postsynaptic density (PSD), 48 chronic intermittent ethanol (CIE), 56 Index neurexins, 49 neuroligins, 49 scaffolding proteins, 48 receptors of, 44 reuptake inhibitor, 51, 55 threo-beta-benzyloxyaspartate (TBOA), 51 synthesis of, 48 transporters of, 47 EAAT1, 47 EAAT2, 47 EAAT3, 47 EAAT4, 47 EAAT5, 47 expression differences for, 66 Glutamate (Glu), Glutamate neurotransmission, 164 Glutamate receptors, 164 desensitization, 214 phosphorylation of, 214 Glutamatergic activity, 44 amino acid transporter (EAAT2), 44 a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), 45 carriers, 47 glutamate/postsynaptic density, 48 glutamate synthesis, 48 glutamate transporter (GLT1), 44 glutamate transporters, 47 ionotropic receptors, 45 metabolism, 48 N-methyl-D-aspartate (NMDA), 45 projections of mesocorticolimbic, 44 receptors, 97 ionotropic, 47 metabotropic, 45 glutamatergic synapse in brain, 44 G-protein-coupled protein receptors (GPCRs), 45 Glutamatergic neurons, 97, 128, 152, 164 Glutamate transporter 1, 164 g-Glutamyl-cysteine-glycine tripeptide, 89 Glutaredoxin, 89, 91 Glutathione, 47 as antioxidant, 47 oxidative stress, 47 Glutathione-S-transferase (GST) family, 89 259 Index Glutathione-S-transferase pi (GSTP), 93 Glutathionylated protein, 91 S-Glutathionylation, 88, 89, 90, 94 in addiction-related protein signaling, 92 in alcohol addiction, 101 of Cdk5, 100 in cocaine addiction, 104 cycle, 89 cysteine residues, 91 of G-actin on cysteine 374, 100 in heroin addiction, 107 of PKC, 99 of proteins, 89, 90 Glycine, 46 GM1, phosphorylation of, 208 GNDF See Glial cell line-derived neurotrophic factor (GNDF) GPCRs See G-protein-coupled protein receptors GPR55 See G-protein-coupled receptor 55 (GPR55) G protein See Guanine-binding regulatory protein (G protein) G-protein-coupled protein receptors (GPCRs), 45 G-protein-coupled receptor 55 (GPR55), 126 G-protein-coupled receptor kinase-3 (GRK3), 127 G protein receptor associated sorting protein-1 (GASP1), 127 G proteins, 208 GRK3 See G-protein-coupled receptor kinase-3 (GRK3) GSH:GSSG ratio, 89, 91, 92 GSH:GSSH ratio, 89 GSH levels, 102 Guanine-binding regulatory protein (G protein), 126 H HDAC5 See Histone deacetylase (HDAC5) Hedonic homeostasis, 152 Heptadecapeptide, 151 Heroin, 97 HIPP See Hippocampus (HIPP) Hippocampus (HIPP), Histone, 235 modification of, 235 proteins, 167 deacetylation of, 167 H3, 167 H4, 167 H2A, 167 H2B, 167 methylation of, 167 Histone deacetylase (HDAC5), 167 Homeostasis, 89 Hot-plate latency, 151 Humans, 231 addictive behavior in, 231 fetal alcohol syndrome in, 245 Hypothalamic–pituitary–adrenal (HPA), 162 I ICSS See Intracranial self-stimulation (ICSS) Icubation phenomenon of drug use, 204 IEG See Immediate early gene (IEG) transcription Immediate early gene (IEG) transcription, Immunohistochemistry, 129 Inhibitory postsynaptic currents (IPSCs), 214 Inositol triphosphate, 94 International Union of Pharmacology (IUPHAR), 151 Intracranial self-stimulation (ICSS), 130 IPSCs See Inhibitory postsynaptic currents (IPSCs) Isoenzymes, 94 IUPHAR See International Union of Pharmacology (IUPHAR) K Kappa agonists, 159 knockdown rats, 59 mGlu2, 60 Knockout models, 186 Kynurenate, 212 260 L LC See Locus coeruleus (LC) Levorphanol, acute administration of, 212 Limbic system, 211 Lipids, 88 Locomotor sensitization, 154, 156 Locus coeruleus (LC), 137, 207 Long-term depression (LTD), 134, 166 Long-term potentiation (LTP), 134, 159 LTD See Long-term depression (LTD) LTP See Long-term potentiation (LTP) M MAPK See Mitogen-activated protein kinases (MAPK) Marijuana, 18 MDMA See 3, 4-methylenedioxymethamphetamine Medial prefrontal cortex (mPFC), 133 Mental health, 47 Mesolimbic dopaminergic neurons 152, 158 Mesolimbic-dopamine system, 185 Metabotropic glutamate receptors (mGluR7), 164 METH See Methamphetamine (METH) Methamphetamine (METH), 3, 16, 92, 93, 153, 237 addictive properties of, 237 cognitive deficits, 17 3, 4-methylenedioxymethamphetamine (MDMA), 237 neurotoxic effects of, 237 novel object recognition (NOR), 17 NSY-1 protein, single nucleotide mutation in, 237 pCREB level, 17 pElk-1 level, 17 pERK level, 17 N-Methyl-D-aspartate (NMDA), 164 3, 4-methylenedioxymethamphetamine (MDMA), 237 Methylnaloxonium, 211 mGlu2, 60 mGlu8, 58 Index genetic risk to develop alcohol dependence, 58 polymorphisms of, 58 mGlu2 polymorphism, 61 mGluR7 See Metabotropic glutamate receptors (mGluR7) Mitogen-activated protein kinases (MAPK), 3, 151, 205 Mitogen- and stress-activated protein kinases (pMSKs), Mn-superoxide dismutase, 102 Molecular changes in brain regions, 211 amygdala, 214 locus coeruleus, 211 periaqueductal gray, 216 CNS regions, 218 ventral tegmental area, 217 Monoamine oxidases, 92 Monoaminergic signaling, 135 Monoaminergic systems, 135 cannabidiol, 137 norepinephrine, 137 serotonin, 135 Morphine, 97, 212 acute administration of, 217 induced antinociception, 206, 208 induced oxidative stress, 109 mPFC See Medial prefrontal cortex (mPFC) N nAChR See Nicotinic acetylcholine receptor nAChRs See Nicotinic acetylcholine receptors (nAChRs) Naloxone opioid receptor antagonist, 161 precipitated withdrawal behavior, 108 Naltrexone, 158 N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), 214 NE See Norepinephrine (NE) Neuroadaptations, 100, 191 Neurochemicals, 158 Neuronal adaptive changes, 150 261 Index Neuronal plasticity, 158 Neuronal synapse, 45 Neuropeptide Y (NPY), 234 Neuroplasticity, 44 Homer, role of, 49 Shank, role of, 49 Zif268, role of, 59 Neurotoxicity, 92, 159 Neurotransmitter systems, 44, 97, 233 norepinephrine, 233 Neurotumor cell line, 212 Nicotine, 20, 235 addiction, 186 chronic oral consumption, 20 coabuse, 188 dopaminergic neurotransmission, 20 mesocorticolimbic dopaminergic system, 21 PFC-NAc projection, 20 pharmacotherapy development in human, 235 structural neuronal plasticity, 20 transient receptor potential (TRP), 235 TRP channel (TRPA1), 235 Nicotinic acetylcholine receptor (nAChR), 184, 235 Nicotinic acetylcholine receptors (nAChRs) genes, 235 Nitric oxide regulation, 91 Nitrosative stress, 89 NMDA See N-methyl-D-aspartate (NMDA) Nociceptin receptor (NOP), 151, 205 agonists, 150, 158 antagonist, 154 knockout mice, 166 Nonassociative cocaine memory, 99 Nonpreferring (NP) rat, 189 NOP See Nociceptin receptor (NOP) NOR See Novel object recognition (NOR) Norepinephrine (NE), 101, 137 Novel object recognition (NOR), 17 NP See Nonpreferring (NP) rat npr-1 variation in, 234 NP rats, 66 Shank2, expression levels of, 66 Shank3, expression levels of, 66 NPY See Neuropeptide Y NTS See Nucleus of solitary tract (NTS) Nucleus accumbens (NAc), 97 Nucleus of solitary tract (NTS), 218 O Octamer-binding transcription factor 1’s (OCT-1), 55 effect of ethanol on, 55 OFQ/N immunoreactivity (OFQ/N-IR), 156 OFQ/N-IR See OFQ/N immunoreactivity (OFQ/N-IR) OFQ/N–NOPr system, 152, 167 Opiates, 231 craving, incubation of, 211 drugs, 99 heroin, 231 morphine, 231 Opioid, 101 abuse, 204 addiction, 94 analgesics, 204 buprenorphine, 204 fentanyl, 204 hydrocodone, 204 hydromorphone, 204 methadone, 204 morphine, 204 oxycodone, 204 induced analgesia, 206 system, 158 treatment, 204 withdrawal, 204 diarrhea, 204 escape attempts, 204 hyperalgesia, 204 ptosis, 204 wet-dog shakes, 204 Opioidergic neurons, 152 m-Opioid receptor (MOPr), 157 antisense oligonucleotides against, 161 Opioid receptor-like (ORL1) receptor, 151, 205 262 m-Opioid receptors, 98 Opioid receptor system, 21, 151, 158, 205 delta, 151 DOP, 205 endogenous, 151 exogenous, 151 kappa, 151 KOP, 205 MOP, 205 mu, 151 ORL1 See Opioid receptor-like (ORL1) receptor Orphanin FQ/nociceptin (OFQ/N), 151 altering glutamate-mediated neuronal plasticity, 164 altering positive reinforcing action of cocaine, 159 as antiopioid peptide, 161 as antistress peptide, 162 anxiolytic effects of, 163 electrophysiologic study of, 166 immunoreactivity (OFQ/N-IR), 156 inhibitory action of, 154 intracerebroventricular administration of, 153 mnemonic effects of, 165 retrodialysis of, 153 Orphanin FQ/Nociceptin/NOPr system, 151 Orphan receptor, 151 Oxidation dopamine, 93 prone polyunsaturated lipids, 88 Oxidative stress, 89, 91–93 Oxidative-stress-induced reduction, 89 P PACAP See Pituitary adenylyl cyclase activating polypeptide (PACAP) PAG See Periaqueductal gray (PAG) Paragigantocellularis (PGi), 211, 213 Parkinson’s disease, 89, 233 pCREB See cAMP response elementbinding protein phosphorylation (pCREB) PDE See Phosphodiesterase (PDE) Index Periaqueductal gray (PAG), 216 pERK signaling, 21 EtOH–mediated, 21 reverses dysfunctional, 17 Pertussis toxin (PTX), 205 PFC See Prefrontal cortex (PFC) PGi See Paragigantocellularis (PGi) Pharmacotherapy, 128, 150 Phenylalanine, 151 Phorbol-12-myristate-13-acetate (PMA), 216 Phosphatidylinositol-4, 5-bisphosphate, 94 Phosphodiesterase (PDE), 206 Phospholipase C, 94 Phosphorylating ribosomal S6 kinases (pRSKs), Phosphorylation, 211 postsynaptic density 95 (PSD95), 97 at Ser845 of AMPARs, 97 of S6K, 100 Phosphorylation of STEP (pSTEP), Pituitary adenylyl cyclase activating polypeptide (PACAP), 159 PKA See Protein kinase A (PKA) PKC See Protein kinase C PKC signaling, 99 Place-conditioning paradigm, 155 Plasticity, 97 Plus maze test, 163 PMA See Phorbol-12-myristate-13acetate (PMA) pMSKs See Mitogen- and stress-activated protein kinases (pMSKs) Polymorphisms, 93 Posterior ventral tegmental area (pVTA), 189 Postsynaptic density (PSD), 48 Postsynaptic dopamine receptors, 94 Posttraumatic stress disorder (PTSD), 135 Potassium channel, BK, 233 PP2A See Protein phosphatase 2A (PP2A) PP2B See Protein phosphatase 2B (PP2B) Prefrontal cortex (PFC), 3, 211 Preprodynorphin, 14 Preproenkephalin, 14 Proaddictive actions, 158 Prohormone convertases, 210 263 Index Promoter, 55 Protein-disulfide isomerase, 89 Protein folding, 90 Protein kinase A (PKA), 205 activator, 99 inhibitors, 99 mediated phosphorylation of serine 897 of GluN1 subunit, 97 signaling, 99 Protein kinase C (PKC), 99, 235 Protein phosphatase-1, 94 Protein phosphatase 2A (PP2A), Protein phosphatase 2B (PP2B), Protein signaling, 88 Proteins, susceptible to S-glutathionylation, 95 Proton magnetic resonance spectroscopy (MRS), 51 pRSKs See Phosphorylating ribosomal S6 kinases (pRSKs) PSD See Postsynaptic density PSD95 clusters, 97 pSTEP See Phosphorylation of STEP (pSTEP) Psychostimulant drugs, 155 Psychostimulants, 100 PTSD See Posttraumatic stress disorder (PTSD) PTX See Pertussis toxin (PTX) PTX-insensitive process, 214 pVTA See Posterior ventral tegmental area (pVTA) R Raf-1 proteins, 211 Reactive nitrogen species (RNS), 88 Reactive oxygen species (ROS), 88, 102 mediated changes to protein thiols, 89 production, 92 Receptor tyrosine kinase (RTK), 211 Redox-sensitive epigenetic modification, 88 Redox-sensitive signaling mechanism, 90 Relapsing brain disorder, 150 RNAi techniques, 232 Ro 64-6198, 157 Rodents, 43, 231 addictions research in, 231 NP rats, 43 P rat, 43 alcohol-associated changes in gene expression, 60 protein expression, 60 ethanol drinking by, 53 RTK See Receptor tyrosine kinase (RTK) S Scaffolding proteins, 48 Homer family of, 49 membrane-associated guanylate kinases (MAGUKs), 48 synaptic plasticity, 48 SCH-23390, 215 dopamine D1 receptor antagonist, 159 Selective serotonin reuptake inhibitors (SSRIs), 190 Self-administer drugs abuse, 164 Serine/threonine kinase, 100 Serotonergic neurons, 160 Serotonergic signaling, 107 Serotonin, 101, 136 Signal transduction, 91, 126 Single nucleotide polymorphisms (SNPs), 43 Slc7a11 promoter, repression of, 55 slo-1 mutation, 233 SNPs See Single nucleotide polymorphisms SSRIs See Selective serotonin reuptake inhibitors (SSRIs) STEP See Striatal-enriched protein tyrosine phosphatase (STEP) Stimulants, 231 amphetamine, 231 cocaine, 231 methamphetamine, 231 nicotine, 231 Stress, 162 circuit, 152 isolation, 162 social defeat, 162 Striatal-enriched protein tyrosine phosphatase (STEP), Sulfiredoxin, 89 Sulfonic acids, 89 264 Index TUNEL-staining, 102 Tyrosine hydroxylase, immunoreactivity of, 218 Tyrosine kinase, 46 SWI/SNF See Conserved switching defective/sucrose nonfermenting SWI/SNF genes, 235 bromodomain containing (BRD7), 235 Synapses, 100 Synaptic plasticity, 97, 100, 133 Systemic cocaine treatment, 153 U T UFP-101, 156 UNC-29, 235 Tail-flick tests, 218 Tetrahydrocannabinol (THC), 18 THC See Tetrahydrocannabinol (THC) Thiol-disulfide oxireductases, 89 Thiol homeostasis, 93 Thioredoxin, 89 Threonine197, dephosphorylation of, 99 Transcription factor, 55, 94 Zif268, 59 Transcription factors, 191 Transgenic models, 186 Transient receptor potential (TRP), 235 Transient receptor potential vanilloid type Ca2+channels (TRPV1), 126 TRP See Transient receptor potential TRPV1 See Transient receptor potential vanilloid type Ca2+channels (TRPV1) V Ventral tegmental area (VTA) 3, 152, 187, 209 Vertebrates, 231 animal modeling of addiction in, 231 Voltage dependent calcium channel (VDCC), 46 VTA See Ventral tegmental area (VTA) W Wild-type mice, 206 Withdrawal jumping, 218 Z ZIP-mediated inhibition, 99 ... recent finding indicating that interference of D1-R/GluN1 association in vitro decreases D1 agonist- and NMDA-induced pERK induction In addition, disrupting the protein– protein interaction in the... each cocaine injection during conditioning) ↓ Expression of CPP (inhibitor was infused before CPP test) ↓ Context- and cocaine priming-induced expression of CPP and ↓ context-induced reinstatement... implicated in drug addiction The chapters in this volume describe some of the latest concepts in emerging and innovative research, discuss new breakthrough findings, define innovative strategies, and