Epigenetic Mechanisms of Drug Addiction

Part of the Research and Perspectives in Neurosciences book series (NEUROSCIENCE)


Drug-induced alterations in gene expression within the reward circuitry of the brain are thought to contribute importantly to the persistence of the drug-addicted state. Recent studies examining the molecular mechanisms by which repeated administration of drugs of abuse induces transcriptional changes have demonstrated a key role for chromatin remodeling and have directly related such chromatin regulation to the promulgation of addictive behaviors. In this review, we discuss recent advances in our understanding of chromatin phenomena—which can be referred to as epigenetics—that contribute to drug addiction, with the goal that such mechanistic insights will aid in the development of novel therapeutics for future treatments of addiction.


Conditioned Place Preference HDAC Inhibition Behavioral Sensitivity Cocaine Administration Cocaine Exposure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by grants from the National Institute on Drug Abuse and contains portions of text taken with permission from Maze and Nestler (2011).


  1. Anderson SM, Famous KR, Sadri-Vakili G, Kumaresan V, Schmidt HD, Bass CE, Terwilliger EF, Cha JH, Pierce RC (2008) CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. Nature Neurosci 11:344–353PubMedCrossRefGoogle Scholar
  2. Baker JH, Maes HH, Larsson H, Lichtenstein P, Kendler KS (2011) Sex differences and developmental stability in genetic and environmental influences on psychoactive substance consumption from early adolescence to young adulthood. Psychol Med 20:1–10Google Scholar
  3. Bateup HS, Santini E, Shen WX, Birnbaum S, Valjent E, Surmeier DJ, Fisone G, Nestler EJ, Greengard P (2010) Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors. Proc Natl Acad Sci USA 107:14845–14850PubMedCrossRefGoogle Scholar
  4. Bird A (2007) Perceptions of epigenetics. Nature 447:396–398PubMedCrossRefGoogle Scholar
  5. Berger SL (2007) The complex language of chromatin regulation during transcription. Nature 447:407–412PubMedCrossRefGoogle Scholar
  6. Berglind WJ, Whitfield TW Jr, LaLumiere RT, Kalivas PW, McGinty JF (2009) A single intra-PFC infusion of BDNF prevents cocaine-induced alterations in extracellular glutamate within the nucleus accumbens. J Neurosci 29:3715–3719PubMedCrossRefGoogle Scholar
  7. Bibb JA, Chen JS, Taylor JR, Svenningsson P, Nishi A, Snyder GL, Yan Z, Sagawa ZK, Ouimet CC, Nairn AC, Nestler EJ, Greengard P (2001) Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410:376–380PubMedCrossRefGoogle Scholar
  8. Black YD, Maclaren FR, Naydenov AV, Carlezon WA Jr, Baxter MG, Konradi C (2006) Altered attention and prefrontal cortex gene expression in rats after binge-like exposure to cocaine during adolescence. J Neurosci 26:9656–9665PubMedCrossRefGoogle Scholar
  9. Borrelli E, Nestler EJ, Allis CD, Sassone-Corsi P (2008) Decoding the epigenetic language of neuronal plasticity. Neuron 60:961–974PubMedCrossRefGoogle Scholar
  10. Brami-Cherrier K, Valjent E, Hervé D, Darragh J, Corvol JC, Pages C, Arthur SJ, Girault JA, Caboche J (2005) Parsing molecular and behavioral effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice. J Neurosci 25:11444–11454PubMedCrossRefGoogle Scholar
  11. Chen BT, Hopf FW, Bonci A (2010) Synaptic plasticity in the mesolimbic system: therapeutic implications for substance abuse. Ann NY Acad Sci 1187:129–139PubMedCrossRefGoogle Scholar
  12. Deng JV, Rodriguiz RM, Hutchinson AN, Kim IH, Wetsel WC, West AE (2010) MeCP2 in the nucleus accumbens contributes to neural and behavioral responses to psychostimulants. Nature Neurosci 13:1128–1136PubMedCrossRefGoogle Scholar
  13. Freeman WM, Patel KM, Brucklacher RM, Lull ME, Erwin M, Morgan D, Roberts DC, Vrana KE (2008) Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration. Neuropsychopharmacology 33:1807–1817PubMedCrossRefGoogle Scholar
  14. Grimm JW, Lu L, Hayashi T, Hope BT, Su TP, Shaham Y (2003) 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 23:742–747PubMedGoogle Scholar
  15. Heiman M, Schaefer A, Gong S, Peterson JD, Day M, Ramsey KE, Suárez-Fariñas M, Schwarz C, Stephan DA, Surmeier DJ, Greengard P, Heintz N (2008) A translational profiling approach for the molecular characterization of CNS cell types. Cell 135:738–748PubMedCrossRefGoogle Scholar
  16. Host L, Dietrich JB, Carouge D, Aunis D, Zwiller J (2009) Cocaine self-administration alters the expression of chromatin-remodelling proteins; modulation by histone deacetylase inhibition. J Psychopharmacol 25:222–229PubMedCrossRefGoogle Scholar
  17. Hyman SE, Malenka RC, Nestler EJ (2006) Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29:565–598PubMedCrossRefGoogle Scholar
  18. Im HI, Hollander JA, Bali P, Kenny PJ (2010) MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212. Nature Neurosci 13:1120–1127PubMedCrossRefGoogle Scholar
  19. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genet 33(Suppl):245–254PubMedCrossRefGoogle Scholar
  20. Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080PubMedCrossRefGoogle Scholar
  21. Kalda A, Heidmets LT, Shen HY, Zharkovsky A, Chen JF (2007) Histone deacetylase inhibitors modulates the induction and expression of amphetamine-induced behavioral sensitization partially through an associated learning of the environment in mice. Behav Brain Res 181:76–84PubMedCrossRefGoogle Scholar
  22. Kalivas PW, Volkow N, Seamans J (2005) Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 45:647–650PubMedCrossRefGoogle Scholar
  23. Koob G, Kreek MJ (2007) Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry 164:1149–1159PubMedCrossRefGoogle Scholar
  24. Kumar A, Choi K-H, Renthal W, Tsankova NM, Theobald DEH, Truong H-T, Russo SJ, LaPlant Q, Sasaki TS, Whistler KN, Neve RL, Self DW, Nestler EJ (2005) Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48:303–314PubMedCrossRefGoogle Scholar
  25. LaPlant Q, Vialou V, Covington HE, Dumitriu D, Feng J, Warren B, Maze I, Dietz DM, Watts EL, Iñiquez SD, Koo JW, Mouzon E, Renthal W, Hollis F, Wang H, Noonan MA, Ren YH, Eisch AJ, Bolaños CA, Kabbaj M, Xiao GH, Neve RL, Hurd YL, Oosting RS, Fan GP, Morrison JH, Nestler EJ (2010) Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nature Neurosci 13:1137–1143PubMedCrossRefGoogle Scholar
  26. LaPlant Q, Nestler EJ (2011) CRACKing the histone code: cocaine’s effects on chromatin structure and function. Hormones Behav 59:321–330CrossRefGoogle Scholar
  27. Levine AA, Guan Z, Barco A, Xu S, Kandel ER, Schwartz JH (2005) CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum. Proc Natl Acad Sci USA 102:19186–19191PubMedCrossRefGoogle Scholar
  28. Lobo MK, Covington HE III, Chaudhury D, Friedman AK, Sun HS, Damez-Werno D, Dietz D, Zaman S, Koo JW, Kennedy PJ, Mouzon E, Mogri M, Neve RL, Deisseroth K, Han MH, Nestler EJ (2010) Cell type specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science 330:385–390PubMedCrossRefGoogle Scholar
  29. Loweth JA, Singer BF, Baker LK, Wilke G, Inamine H, Bubula N, Alexander JK, Carlezon WA Jr, Neve RL, Vezina P (2010) Transient overexpression of alpha-Ca2+/calmodulin-dependent protein kinase II in the nucleus accumbens shell enhances behavioral responding to amphetamine. J Neurosci 30:939–949PubMedCrossRefGoogle Scholar
  30. Malvaez M, Sanchis-Segura C, Vo D, Lattal KM, Wood MA (2010) Modulation of chromatin modification facilitates extinction of cocaine-induced conditioned place preference. Biol Psychiat 67:36–43PubMedCrossRefGoogle Scholar
  31. Maze I, Nestler EJ (2011) The epigenetic landscape of addiction. Ann NY Acad Sci 1216:99–113PubMedCrossRefGoogle Scholar
  32. Maze I, Russo SJ (2010) Transcriptional mechanisms underlying addiction-related structural plasticity. Mol Interv 10:219–230PubMedCrossRefGoogle Scholar
  33. Maze I, Covington HE III, Dietz DM, LaPlant Q, Renthal W, Russo SJ, Mechanic M, Mouzon E, Neve RL, Haggarty SJ, Ren YH, Sampath SC, Hurd YL, Greengard P, Tarakovsky A, Schaefer A, Nestler EJ (2010) Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science 327:213–216PubMedCrossRefGoogle Scholar
  34. Maze I, Feng J, Wilkinson MB, Sun HS, Shen L, Nestler EJ (2011) Cocaine dynamically regulates heterochromatin formation and repetitive element unsilencing in nucleus accumbens. Proc Natl Acad Sci USA 108:3035–3040PubMedCrossRefGoogle Scholar
  35. McQuown SC, Wood MA (2010) Epigenetic regulation in substance use disorders. Curr Psychiatry Rep 12:145–153PubMedCrossRefGoogle Scholar
  36. Nestler EJ (2001) Molecular basis of long-term plasticity underlying addiction. Nature Rev Neurosci 2:119–128CrossRefGoogle Scholar
  37. Nestler EJ (2008) Transcriptional mechanisms of addiction: role of DeltaFosB. Philos Trans R Soc Lond B Biol Sci 363:3245–3255PubMedCrossRefGoogle Scholar
  38. Norrholm SD, Bibb JA, Nestler EJ, Ouimet CC, Taylor JR, Greengard P (2003) Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5. Neuroscience 116:19–22PubMedCrossRefGoogle Scholar
  39. Novikova SI, He F, Bai J, Cutrufello NJ, Lidow MS, Undieh AS (2008) Maternal cocaine administration in mice alters DNA methylation and gene expression in hippocampal neurons of neonatal and prepubertal offspring. PLoS One 3:e1919PubMedCrossRefGoogle Scholar
  40. Pulipparacharuvil S, Renthal W, Hale CF, Taniguchi M, Xiao GH, Kumar A, Russo SJ, Sikder D, Dewey CM, Davis MM, Greengard P, Nairn AC, Nestler EJ, Cowan CW (2008) Cocaine regulates MEF2 to control synaptic and behavioral plasticity. Neuron 59:621–633PubMedCrossRefGoogle Scholar
  41. Renthal W, Nestler EJ (2008) Epigenetic mechanisms in drug addiction. Trends Mol Med 14:341–350PubMedCrossRefGoogle Scholar
  42. Renthal W, Maze I, Krishnan V, Covington HE, Xiao GH, Kumar A, Russo SJ, Graham A, Tsankova N, Kerstetter KA, Kippin TE, Neve RL, Haggarty SJ, McKinsey TA, Bassel-Duby R, Olson EN, Nestler EJ (2007) Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli. Neuron 56:517–529PubMedCrossRefGoogle Scholar
  43. Renthal W, Carle TL, Maze I, Covington HE III, Truong HT, Alibhai I, Kumar A, Olson EN, Nestler EJ (2008) Delta FosB mediates epigenetic desensitization of the c-fos gene after chronic amphetamine exposure. J Neurosci 28:7344–7349PubMedCrossRefGoogle Scholar
  44. Renthal W, Kumar A, Xiao GH, Wilkinson M, Convington HE III, Maze I, Sikder D, Robison AJ, LaPlant Q, Dietz DM, Russo SJ, Vialou V, Chakravarty S, Kodadek TJ, Stack A, Kabbaj M, Nestler EJ (2009) Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins. Neuron 62:335–348PubMedCrossRefGoogle Scholar
  45. Robinson TE, Kolb B (2004) Structural plasticity associated with exposure to drugs of abuse. Neuropharmacol 47:S33–S46CrossRefGoogle Scholar
  46. Romieu P, Host L, Gobaille S, Sandner G, Aunis D, Zwiller J (2008) Histone deacetylase inhibitors decrease cocaine but not sucrose self-administration in rats. J Neurosci 28:9342–9348PubMedCrossRefGoogle Scholar
  47. Russo SJ, Dietz DM, Dumitriu D, Malenka RC, Morrison JH, Nestler EJ (2010) The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci 33:267–276PubMedCrossRefGoogle Scholar
  48. Sanchis-Segura C, Lopez-Atalaya JP, Barco A (2009) Selective boosting of transcriptional and behavioral responses to drugs of abuse by histone deacetylase inhibition. Neuropsychopharmacol 34:2642–2654CrossRefGoogle Scholar
  49. Schroeder FA, Penta KL, Matevossian A, Jones SR, Konradi C, Tapper AR, Akbarian S (2008) Drug-induced activation of dopamine D(1) receptor signaling and inhibition of class I/II histone deacetylase induce chromatin remodeling in reward circuitry and modulate cocaine-related behaviors. Neuropsychopharmacology 33:2981–2992PubMedCrossRefGoogle Scholar
  50. Self DW, Barnhart WJ, Lehman DA, Nestler EJ (1996) Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Science 271:1586–1589PubMedCrossRefGoogle Scholar
  51. Stipanovich A, Valjent E, Matamales M, Nishi A, Ahn JH, Maroteaux M, Bertran-Gonzalez J, Brami-Cherrier K, Enslen H, Corbillé AG, Filhol O, Nairn AC, Greengard P, Hervé D, Girault JA (2008) A phosphatase cascade by which rewarding stimuli control nucleosomal response. Nature 453:879–884PubMedCrossRefGoogle Scholar
  52. Sun J, Wang L, Jiang B, Hui B, Lv Z, Ma L (2008) The effects of sodium butyrate, an inhibitor of histone deacetylase, on the cocaine- and sucrose-maintained self-administration in rats. Neurosci Lett 441:72–76PubMedCrossRefGoogle Scholar
  53. Surmeier DJ, Ding J, Day M, Wang Z, Shen W (2007) D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci 30:228–235PubMedCrossRefGoogle Scholar
  54. Thomas MJ, Beurrier C, Bonci A, Malenka RC (2001) Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine. Nat Neurosci 4:1217–1223PubMedCrossRefGoogle Scholar
  55. Wang L, Lv Z, Hu Z, Sheng J, Hui B, Sun J, Ma L (2010) Chronic cocaine-induced H3 acetylation and transcriptional activation of CaMKIIalpha in the nucleus accumbens is critical for motivation for drug reinforcement. Neuropsychopharmacology 35:913–928PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Laboratory of Chromatin Biology and EpigeneticsThe Rockefeller UniversityNew YorkUSA
  2. 2.Fishberg Department of NeuroscienceMount Sinai School of MedicineNew YorkUSA

Personalised recommendations