Epigenetic mechanisms of drug addiction - PubMed (original) (raw)

Review

Epigenetic mechanisms of drug addiction

Jian Feng et al. Curr Opin Neurobiol. 2013 Aug.

Abstract

Epigenetic regulation can mediate long-lasting changes in gene expression, which makes it an attractive mechanism for the stable behavioral abnormalities that characterize drug addiction. Recent research has unveiled numerous types of epigenetic modifications within the brain's reward circuitry in animal models of drug addiction. In this review, we summarize the latest advances in the field, focusing on histone modifications, DNA methylation, and noncoding RNAs. We also highlight several areas for future research. Unraveling the highly complex epigenetic mechanisms of addiction is adding to our understanding of this syndrome and has the potential to trigger novel approaches for better diagnosis and therapy.

Copyright © 2013 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1. Histone posttranslational modifications

(A) The nucleosome core particle composed of 147 bp of DNA wrapped around an octamer of histone proteins (two copies each of H2A, H2B, H3, and H4). (B) Histone modifications on histone H3 tail. Permissive gene expression correlates with modifications that weaken the interaction between histones and DNA or that promote the recruitment of transcriptional activating complexes (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). Repressive transcription correlates with histone deacetylation (which compacts nucleosomes), histone methylation (e.g., on H3K27 or H3K9, which recruits repressive complexes to chromatin), or DNA methylation (not shown).

Figure 2

Figure 2. Mechanisms of transcriptional and epigenetic regulation by drugs of abuse

Drugs of abuse act through synaptic targets (reuptake mechanisms, ion channels, and neurotransmitter [NT] receptors) to alter intracellular signalling cascades. This leads to the activation or inhibition of transcription factors and of many other nuclear targets, including chromatin-regulatory proteins (shown by thick arrows). These processes result in the induction or repression of particular genes, which can in turn further regulate gene transcription. It is proposed that some of these drug-induced changes at the chromatin level are extremely stable and thereby underlie the long-lasting behaviours that define addiction. CREB, cAMP-response element binding protein; DNMTs, DNA methyltransferases; HATs, histone acetyltransferases; HDACs, histone deacetylases; HDMs, histone demethylases; HMTs, histone methyltransferases; MEF2, myocyte-specific enhancer factor 2; NF-κB, nuclear factor-κB; pol II, RNA polymerase II. Figure is reproduced with permission from Ref.

Figure 3

Figure 3. Gene priming and desensitization

Epigenetic mechanisms are important in mediating gene priming and desensitization, which are not reflected by stable changes in steady-state mRNA levels. Instead, a later drug challenge induces a given gene to a greater (primed) or lesser (desensitized) extent based on the epigenetic modifications that are induced by previous chronic drug exposure. A, acetylation; M, methylation; P, phosphorylation; pol II, RNA polymerase II. Figure is reproduced with permission from Ref. .

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