The epigenetic landscape of addiction

Abstract

Drug-induced alterations in gene expression throughout the reward circuitry of the brain are likely components of the persistence of the drug-addicted state. Recent studies examining the molecular mechanisms controlling drug-induced transcriptional, behavioral, and synaptic plasticity have indicated a direct role for chromatin remodeling in the regulation and stability of drug-mediated neuronal gene programs, and the subsequent promulgation of addictive behaviors. In this review, we discuss recent advances in our understanding of chromatin phenomena--or epigenetics, by one definition--that contribute to drug addiction, with the hope that such mechanistic insights may aid in the development of novel therapeutics for future treatments of addiction.

Figure 1

Post-translational modifications of histones regulate gene expression. Shown in panel (A) is the nucleosome core particle, representing the functional repeating unit of chromatin, composed of 147 bp of DNA wrapped around a core octamer of histone proteins (two copies each of H2A, H2B, H3 and H4). (B) Combinations of acetylation, phosphorylation, methylation, etc. on histone tails (here, H3 is depicted) alter chromatin compaction promoting altered levels of gene expression in cells. Histone modifications that weaken the interaction between histones and DNA (e.g., histone acetylation at K23, K18, K14, and K9, as well as methylation at K79, K36, and K4 or phosphorylation at S28 and S10) correlate with permissive gene expression. Histone deacetylation or histone methylation on H3K27 or H3K9, which strengthen histone:DNA contacts, promote a state of transcriptional repression. Figure 1 (adapted) from Maze I. & Russo, S.J. 2010. Transcriptional mechanisms underlying addiction-related structural plasticity. Molecular Interventions. In Press. with permission.

Figure 2

Chronic cocaine exposure alters genome-wide patterns of histone modifications and transcription factor binding in NAc. (A) Venn diagrams and (B) heat maps depicting genes displaying altered levels of H3 or H4 acetylation and H3 methylation (dimethyl-K9/K27) promoter occupancy 24 hr after chronic cocaine administration. (C) Venn diagrams of genes displaying significant promoter binding of the transcription factor ΔFosB, and/or of H3/H4 acetylation or H3 methylation in NAc, following chronic cocaine administration. Figure 2 (adapted) from with permission.

Figure 3

Cocaine-induced disruption of repressive histone modifying enzymes in NAc results in enhanced behavioral plasticity. (A) Intra-NAc delivery of the specific HDACi suberoylanilide hydroxamic acid (SAHA) significantly potentiates conditioned place preference (CPP) for cocaine. (B) Cocaine-naive HDAC5 KO mice do not show a greater preference for cocaine in comparison to their wildtype littermate controls, however, after prior exposure to cocaine, HDAC5 KO mice develop a significant hypersensitization to cocaine reward. Viral-mediated knockdown of (C) the histone methyltransferase G9a or (D) the DNA methyltransferase DNMT3a in NAc, results in significantly enhanced CPP for cocaine. Figure 3 (adapted) from ^{(D),(A & B),(C)} with permission.

Figure 4

Chronic cocaine administration increases both transcriptional and structural plasticity in NAc through chromatin dependent mechanisms. (A) Analysis of gene expression after acute or repeated cocaine indicates increased transcriptional activation/inducibility in NAc. Heat maps (*) display genes up-regulated in NAc 1 hour after a cocaine challenge in naïve animals (acute), in animals treated repeatedly with cocaine (chronic + challenge), or in animals after 7 days of withdrawal from chronic cocaine (chronic wd + challenge). Associated heat maps show how genes are affected under the other two conditions. (B) Methylation of H3K9 promotes chromatin condensation and gene repression. Following either saline or acute cocaine exposure, a complex of HMTs, mainly G9a and GLP, along with HDACs (e.g., HDAC5) bind to histones and repress transcription. After chronic cocaine administration, however, repressive HMT and HDAC binding to plasticity related gene promoters is reduced, which, in combination with increased kinase activity and binding of HATs, ΔFosB, pCREB and RNA polymerase lI (Pol II), results in a permissive state of transcription. Such decreased binding of repressive chromatin complexes results in increased structural plasticity on NAc MSNs. (C) Overexpression of G9a in NAc, which opposes the endogenous effects of cocaine, blocks cocaine-induced alterations in transcription and significantly reduces structural plasticity in this brain region. Figure 4 (adapted) from ^{(A & C)} and Maze I. & Russo, S.J. 2010. Transcriptional mechanisms underlying addiction-related structural plasticity. Molecular Interventions. In Press. with permission.