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Epigenetic Mechanisms in Drug Relapse

      Abstract

      A growing body of evidence from the past 15 years implicates epigenetic mechanisms in the behavioral effects of addictive drugs. The main focus of these studies has been epigenetic mechanisms of psychomotor sensitization and drug reinforcement, as assessed by the conditioned place preference and drug self-administration procedures. Some of these studies have documented long-lasting changes in the expression of epigenetic enzymes and molecules that persist for weeks after the last drug exposure. These observations have inspired more recent investigations on the epigenetic mechanisms of relapse to drug seeking after prolonged abstinence.
      Here, we review studies that have examined epigenetic mechanisms (e.g., histone modifications, chromatin remodeler–associated modifications, and DNA methylation) that contribute to relapse to cocaine, amphetamine, methamphetamine, morphine, heroin, nicotine, or alcohol seeking, as assessed in rodent models. We first provide a brief overview of studies that have examined persistent epigenetic changes in the brain after prolonged abstinence from noncontingent drug exposure or drug self-administration. Next, we review studies on the effect of either systemic or brain site–specific epigenetic manipulations on the reinstatement of drug-conditioned place preference after extinction of the learned preference, the reinstatement of drug seeking after operant drug self-administration and extinction of the drug-reinforced responding, and the incubation of drug craving (the time-dependent increase in drug seeking after cessation of drug self-administration). We conclude by discussing the implications of these studies for understanding mechanisms contributing to persistent relapse vulnerability after prolonged abstinence. We also discuss the implications of these results for translational research on the potential use of systemically administered epigenetic enzyme inhibitors for relapse prevention in human drug users.

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      References

        • Kumar A.
        • Choi K.H.
        • Renthal W.
        • Tsankova N.M.
        • Theobald D.E.
        • Truong H.T.
        • et al.
        Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum.
        Neuron. 2005; 48: 303-314
        • Feng J.
        • Nestler E.J.
        Epigenetic mechanisms of drug addiction.
        Curr Opin Neurobiol. 2013; 23: 521-528
        • Hamilton P.J.
        • Nestler E.J.
        Epigenetics and addiction.
        Curr Opin Neurobiol. 2019; 59: 128-136
        • Nestler E.J.
        Epigenetic mechanisms of drug addiction.
        Neuropharmacology. 2014; 76: 259-268
        • Renthal W.
        • Nestler E.J.
        Epigenetic mechanisms in drug addiction.
        Trends Mol Med. 2008; 14: 341-350
        • Renthal W.
        • Nestler E.J.
        Histone acetylation in drug addiction.
        Semin Cell Dev Biol. 2009; 20: 387-394
        • Walker D.M.
        • Cates H.M.
        • Heller E.A.
        • Nestler E.J.
        Regulation of chromatin states by drugs of abuse.
        Curr Opin Neurobiol. 2015; 30: 112-121
        • Rogge G.A.
        • Wood M.A.
        The role of histone acetylation in cocaine-induced neural plasticity and behavior.
        Neuropsychopharmacology. 2013; 38: 94-110
        • Robison A.J.
        • Nestler E.J.
        Transcriptional and epigenetic mechanisms of addiction.
        Nat Rev Neurosci. 2011; 12: 623-637
        • De Sa Nogueira D.
        • Merienne K.
        • Befort K.
        Neuroepigenetics and addictive behaviors: Where do we stand?.
        Neurosci Biobehav Rev. 2019; 106: 58-72
        • Stewart A.F.
        • Fulton S.L.
        • Maze I.
        Epigenetics of drug addiction.
        Cold Spring Harb Perspect Med a040253. 2020;
        • Hunt W.A.
        • Barnett L.W.
        • Branch L.G.
        Relapse rates in addiction programs.
        J Clin Psychol. 1971; 27: 455-456
        • Sinha R.
        New findings on biological factors predicting addiction relapse vulnerability.
        Curr Psychiatry Rep. 2011; 13: 398-405
        • Kenny P.J.
        Epigenetics, microRNA, and addiction.
        Dialogues Clin Neurosci. 2014; 16: 335-344
        • Smith A.C.W.
        • Kenny P.J.
        MicroRNAs regulate synaptic plasticity underlying drug addiction.
        Genes Brain Behav. 2018; 17e12424
        • Li M.D.
        • van der Vaart A.D.
        MicroRNAs in addiction: Adaptation's middlemen?.
        Mol Psychiatry. 2011; 16: 1159-1168
        • Mucha R.F.
        • van der Kooy D.
        • O'Shaughnessy M.
        • Bucenieks P.
        Drug reinforcement studied by the use of place conditioning in rat.
        Brain Res. 1982; 243: 91-105
        • Mueller D.
        • Stewart J.
        Cocaine-induced conditioned place preference: Reinstatement by priming injections of cocaine after extinction.
        Behav Brain Res. 2000; 115: 39-47
        • Parker L.A.
        • McDonald R.V.
        Reinstatement of both a conditioned place preference and a conditioned place aversion with drug primes.
        Pharmacol Biochem Behav. 2000; 66: 559-561
        • Malvaez M.
        • Sanchis-Segura C.
        • Vo D.
        • Lattal K.M.
        • Wood M.A.
        Modulation of chromatin modification facilitates extinction of cocaine-induced conditioned place preference.
        Biol Psychiatry. 2010; 67: 36-43
        • Malvaez M.
        • McQuown S.C.
        • Rogge G.A.
        • Astarabadi M.
        • Jacques V.
        • Carreiro S.
        • et al.
        HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner.
        Proc Natl Acad Sci U S A. 2013; 110: 2647-2652
        • Wang R.
        • Zhang Y.
        • Qing H.
        • Liu M.
        • Yang P.
        The extinction of morphine-induced conditioned place preference by histone deacetylase inhibition.
        Neurosci Lett. 2010; 483: 137-142
        • Zhu J.
        • Zhao N.
        • Chen Y.
        • Zhu L.
        • Zhong Q.
        • Liu J.
        • et al.
        Sodium butyrate modulates a methamphetamine-induced conditioned place preference.
        J Neurosci Res. 2017; 95: 1044-1052
        • Itzhak Y.
        • Liddie S.
        • Anderson K.L.
        Sodium butyrate-induced histone acetylation strengthens the expression of cocaine-associated contextual memory.
        Neurobiol Learn Mem. 2013; 102: 34-42
        • Zhang Y.X.
        • Akumuo R.C.
        • Espana R.A.
        • Yan C.X.
        • Gao W.J.
        • Li Y.C.
        The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory.
        Neuropharmacology. 2018; 141: 113-125
        • Guo W.
        • Long H.
        • Bu Q.
        • Zhao Y.
        • Wang H.
        • Tian J.
        • et al.
        Role of BRD4 phosphorylation in the nucleus accumbens in relapse to cocaine-seeking behavior in mice.
        Addict Biol. 2020; 25e12808
        • Lax E.
        • Friedman A.
        • Massart R.
        • Barnea R.
        • Abraham L.
        • Cheishvili D.
        • et al.
        PARP-1 is required for retrieval of cocaine-associated memory by binding to the promoter of a novel gene encoding a putative transposase inhibitor.
        Mol Psychiatry. 2017; 22: 570-579
        • Aguilar-Valles A.
        • Vaissiere T.
        • Griggs E.M.
        • Mikaelsson M.A.
        • Takacs I.F.
        • Young E.J.
        • et al.
        Methamphetamine-associated memory is regulated by a writer and an eraser of permissive histone methylation.
        Biol Psychiatry. 2014; 76: 57-65
        • Wang Y.
        • Lai J.
        • Cui H.
        • Zhu Y.
        • Zhao B.
        • Wang W.
        • et al.
        Inhibition of histone deacetylase in the basolateral amygdala facilitates morphine context-associated memory formation in rats.
        J Mol Neurosci. 2015; 55: 269-278
        • Lopez A.J.
        • Hemstedt T.J.
        • Jia Y.
        • Hwang P.H.
        • Campbell R.R.
        • Kwapis J.L.
        • et al.
        Epigenetic regulation of immediate-early gene Nr4a2/Nurr1 in the medial habenula during reinstatement of cocaine-associated behavior.
        Neuropharmacology. 2019; 153: 13-19
        • Shaham Y.
        • Shalev U.
        • Lu L.
        • de Wit H.
        • Stewart J.
        The reinstatement model of drug relapse: History, methodology and major findings.
        Psychopharmacology (Berl). 2003; 168: 3-20
        • Crombag H.S.
        • Bossert J.M.
        • Koya E.
        • Shaham Y.
        Context-induced relapse to drug seeking: A review.
        Philos Trans R Soc Lond B Biol Sci. 2008; 363: 3233-3243
        • Mantsch J.R.
        • Baker D.A.
        • Funk D.
        • Lê A.D.
        • Shaham Y.
        Stress-induced reinstatement of drug seeking: 20 years of progress.
        Neuropsychopharmacology. 2016; 41: 335-356
        • See R.E.
        Neural substrates of conditioned-cued relapse to drug-seeking behavior.
        Pharmacol Biochem Behav. 2002; 71: 517-529
        • Self D.W.
        • Choi K.H.
        • Simmons D.
        • Walker J.R.
        • Smagula C.S.
        Extinction training regulates neuroadaptive responses to withdrawal from chronic cocaine self-administration.
        Learn Mem. 2004; 11: 648-657
        • Wolf M.E.
        • Ferrario C.R.
        AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine.
        Neurosci Biobehav Rev. 2010; 35: 185-211
        • Romieu P.
        • Deschatrettes E.
        • Host L.
        • Gobaille S.
        • Sandner G.
        • Zwiller J.
        The inhibition of histone deacetylases reduces the reinstatement of cocaine-seeking behavior in rats.
        Curr Neuropharmacol. 2011; 9: 21-25
        • Chen W.S.
        • Xu W.J.
        • Zhu H.Q.
        • Gao L.
        • Lai M.J.
        • Zhang F.Q.
        • et al.
        Effects of histone deacetylase inhibitor sodium butyrate on heroin seeking behavior in the nucleus accumbens in rats.
        Brain Res. 2016; 1652: 151-157
        • Peterson A.B.
        • Abel J.M.
        • Lynch W.J.
        Dose-dependent effects of wheel running on cocaine-seeking and prefrontal cortex Bdnf exon IV expression in rats.
        Psychopharmacology (Berl). 2014; 231: 1305-1314
        • Arndt D.L.
        • Wukitsch T.J.
        • Garcia E.J.
        • Cain M.
        Histone deacetylase inhibition differentially attenuates cue-induced reinstatement: An interaction of environment and acH3K9 expression in the dorsal striatum.
        Behav Neurosci. 2019; 133: 478-488
        • Monsey M.S.
        • Ruiz S.G.
        • Taylor J.R.
        Regulation of garcinol on histone acetylation in the amygdala and on the reconsolidation of a cocaine-associated memory.
        Front Behav Neurosci. 2020; 13: 281
        • Monsey M.S.
        • Sanchez H.
        • Taylor J.R.
        The naturally occurring compound garcinia indica selectively impairs the reconsolidation of a cocaine-associated memory.
        Neuropsychopharmacology. 2017; 42: 587-597
        • Castino M.R.
        • Cornish J.L.
        • Clemens K.J.
        Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats.
        PLoS One. 2015; 10e0124796
        • Wright K.N.
        • Hollis F.
        • Duclot F.
        • Dossat A.M.
        • Strong C.E.
        • Francis T.C.
        • et al.
        Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c-Fos activation in a DNA methylation-dependent manner.
        J Neurosci. 2015; 35: 8948-8958
        • Hitchcock L.N.
        • Raybuck J.D.
        • Wood M.A.
        • Lattal K.M.
        Effects of a histone deacetylase 3 inhibitor on extinction and reinstatement of cocaine self-administration in rats.
        Psychopharmacology (Berl). 2019; 236: 517-529
        • Martin J.A.
        • Werner C.T.
        • Mitra S.
        • Zhong P.
        • Wang Z.J.
        • Gobira P.H.
        • et al.
        A novel role for the actin-binding protein drebrin in regulating opiate addiction.
        Nat Commun. 2019; 10: 4140
        • Taniguchi M.
        • Carreira M.B.
        • Cooper Y.A.
        • Bobadilla A.C.
        • Heinsbroek J.A.
        • Koike N.
        • et al.
        HDAC5 and its target gene, Npas4, function in the nucleus accumbens to regulate cocaine-conditioned behaviors.
        Neuron. 2017; 96: 130-144, e136
        • Anderson E.M.
        • Larson E.B.
        • Guzman D.
        • Wissman A.M.
        • Neve R.L.
        • Nestler E.J.
        • et al.
        Overexpression of the histone dimethyltransferase G9a in nucleus accumbens shell increases cocaine self-administration, stress-induced reinstatement, and anxiety.
        J Neurosci. 2018; 38: 803-813
        • Anderson E.M.
        • Sun H.
        • Guzman D.
        • Taniguchi M.
        • Cowan C.W.
        • Maze I.
        • et al.
        Knockdown of the histone di-methyltransferase G9a in nucleus accumbens shell decreases cocaine self-administration, stress-induced reinstatement, and anxiety.
        Neuropsychopharmacology. 2019; 44: 1370-1376
        • Gancarz A.M.
        • Wang Z.J.
        • Schroeder G.L.
        • Damez-Werno D.
        • Braunscheidel K.M.
        • Mueller L.E.
        • et al.
        Activin receptor signaling regulates cocaine-primed behavioral and morphological plasticity.
        Nat Neurosci. 2015; 18: 959-961
        • Wang Z.J.
        • Martin J.A.
        • Mueller L.E.
        • Caccamise A.
        • Werner C.T.
        • Neve R.L.
        • et al.
        BRG1 in the nucleus accumbens regulates cocaine-seeking behavior.
        Biol Psychiatry. 2016; 80: 652-660
        • Shi H.S.
        • Luo Y.X.
        • Yin X.
        • Wu H.H.
        • Xue G.
        • Geng X.H.
        • et al.
        Reconsolidation of a cocaine associated memory requires DNA methyltransferase activity in the basolateral amygdala.
        Sci Rep. 2015; 5: 13327
        • Barbier E.
        • Johnstone A.L.
        • Khomtchouk B.B.
        • Tapocik J.D.
        • Pitcairn C.
        • Rehman F.
        • et al.
        Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2.
        Mol Psychiatry. 2017; 22: 1746-1758
        • Grimm J.W.
        • Hope B.T.
        • Wise R.A.
        • Shaham Y.
        Neuroadaptation. Incubation of cocaine craving after withdrawal.
        Nature. 2001; 412: 141-142
        • Grimm J.W.
        • Lu L.
        • Hayashi T.
        • Hope B.T.
        • Su T.P.
        • Shaham Y.
        Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: Implications for incubation of cocaine craving.
        J Neurosci. 2003; 23: 742-747
        • Lu L.
        • Grimm J.W.
        • Dempsey J.
        • Shaham Y.
        Cocaine seeking over extended withdrawal periods in rats: Different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months.
        Psychopharmacology (Berl). 2004; 176: 101-108
        • Lu L.
        • Grimm J.W.
        • Hope B.T.
        • Shaham Y.
        Incubation of cocaine craving after withdrawal: A review of preclinical data.
        Neuropharmacology. 2004; 47: 214-226
        • Wolf M.E.
        Synaptic mechanisms underlying persistent cocaine craving.
        Nat Rev Neurosci. 2016; 17: 351-365
        • Pickens C.L.
        • Airavaara M.
        • Theberge F.
        • Fanous S.
        • Hope B.T.
        • Shaham Y.
        Neurobiology of the incubation of drug craving.
        Trends Neurosci. 2011; 34: 411-420
        • Cannella N.
        • Oliveira A.M.M.
        • Hemstedt T.
        • Lissek T.
        • Buechler E.
        • Bading H.
        • et al.
        Dnmt3a2 in the nucleus accumbens shell is required for reinstatement of cocaine seeking.
        J Neurosci. 2018; 38: 7516-7528
        • Knackstedt L.A.
        • Moussawi K.
        • Lalumiere R.
        • Schwendt M.
        • Klugmann M.
        • Kalivas P.W.
        Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine seeking.
        J Neurosci. 2010; 30: 7984-7992
        • Sutton M.A.
        • Schmidt E.F.
        • Choi K.H.
        • Schad C.A.
        • Whisler K.
        • Simmons D.
        • et al.
        Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour.
        Nature. 2003; 421: 70-75
        • Fuchs R.A.
        • Branham R.K.
        • See R.E.
        Different neural substrates mediate cocaine seeking after abstinence versus extinction training: A critical role for the dorsolateral caudate-putamen.
        J Neurosci. 2006; 26: 3584-3588
        • Shaham Y.
        • Hope B.T.
        The role of neuroadaptations in relapse to drug seeking.
        Nat Neurosci. 2005; 8: 1437-1439
        • Massart R.
        • Barnea R.
        • Dikshtein Y.
        • Suderman M.
        • Meir O.
        • Hallett M.
        • et al.
        Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving.
        J Neurosci. 2015; 35: 8042-8058
        • Werner C.T.
        • Mitra S.
        • Martin J.A.
        • Stewart A.F.
        • Lepack A.E.
        • Ramakrishnan A.
        • et al.
        Ubiquitin-proteasomal regulation of chromatin remodeler INO80 in the nucleus accumbens mediates persistent cocaine craving.
        Sci Adv. 2019; 5eaay0351
        • Carpenter M.D.
        • Hu Q.
        • Bond A.M.
        • Lombroso S.I.
        • Czarnecki K.S.
        • Lim C.J.
        • et al.
        Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes.
        Nat Commun. 2020; 11: 504
        • Lepack A.E.
        • Werner C.T.
        • Stewart A.F.
        • Fulton S.L.
        • Zhong P.
        • Farrelly L.A.
        • et al.
        Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking.
        Science. 2020; 368: 197-201
        • Li X.
        • Carreria M.B.
        • Witonsky K.R.
        • Zeric T.
        • Lofaro O.M.
        • Bossert J.M.
        • et al.
        Role of dorsal striatum histone deacetylase 5 in incubation of methamphetamine craving.
        Biol Psychiatry. 2018; 84: 213-222
        • Maze I.
        • Shen L.
        • Zhang B.
        • Garcia B.A.
        • Shao N.
        • Mitchell A.
        • et al.
        Analytical tools and current challenges in the modern era of neuroepigenomics.
        Nat Neurosci. 2014; 17: 1476-1490
        • Cates H.M.
        • Li X.
        • Purushothaman I.
        • Kennedy P.J.
        • Shen L.
        • Shaham Y.
        • et al.
        Genome-wide transcriptional profiling of central amygdala and orbitofrontal cortex during incubation of methamphetamine craving.
        Neuropsychopharmacology. 2018; 43: 2426-2434
        • Walker D.M.
        • Cates H.M.
        • Loh Y.E.
        • Purushothaman I.
        • Ramakrishnan A.
        • Cahill K.M.
        • et al.
        Cocaine self-administration alters transcriptome-wide responses in the brain's reward circuitry.
        Biol Psychiatry. 2018; 84: 867-880
        • Li X.
        • Rubio F.J.
        • Zeric T.
        • Bossert J.M.
        • Kambhampati S.
        • Cates H.M.
        • et al.
        Incubation of methamphetamine craving is associated with selective increases in expression of Bdnf and TrkB, glutamate receptors, and epigenetic enzymes in cue-activated fos-expressing dorsal striatal neurons.
        J Neurosci. 2015; 35: 8232-8244
        • Kalivas P.W.
        • LaLumiere R.T.
        • Knackstedt L.
        • Shen H.W.
        Glutamate transmission in addiction.
        Neuropharmacology. 2009; 56: 169-173
        • Torregrossa M.M.
        • Taylor J.R.
        Learning to forget: Manipulating extinction and reconsolidation processes to treat addiction.
        Psychopharmacology (Berl). 2013; 226: 659-672
        • Milton A.L.
        • Everitt B.J.
        The psychological and neurochemical mechanisms of drug memory reconsolidation: Implications for the treatment of addiction.
        Eur J Neurosci. 2010; 31: 2308-2319