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, 12 (2), 145-53

Epigenetic Regulation in Substance Use Disorders


Epigenetic Regulation in Substance Use Disorders

Susan C McQuown et al. Curr Psychiatry Rep.


Substance use disorder is a chronic condition of compulsive drug seeking and use that is mediated by stable changes in central reward pathways. Repeated use of abused drugs causes persistent alterations in gene expression responsible for the long-term behavioral and structural changes. Recently, it has been suggested that epigenetic mechanisms are responsible in part for these drug-induced changes in gene expression. One of the alluring aspects of epigenetic regulation of gene expression is that epigenetic mechanisms may provide transient and potentially stable conditions that in turn may ultimately participate in the molecular mechanisms required for neuronal changes subserving long-lasting changes in behavior. This review describes epigenetic mechanisms of gene regulation and then discusses the emerging role of epigenetics in drug-induced plasticity and behavior. Understanding these mechanisms that establish and maintain drug-dependent plasticity changes may lead to deeper understanding of substance use disorders as well as novel approaches to treatment.


Fig. 1
Fig. 1
Histone acetyltransferases (HATs) and histone deacetylases (HDACs) have opposing activities. Nucleosomes, shown as blue barrels, are composed of histone octamers that are involved in binding DNA. Histone N-terminal tails, shown in purple (left nucleosome) or in green (right nucleosome), contain residues that directly interact with the genomic DNA. In a transcriptionally silent state (left nucleosome), positively charged lysine residues interact with the negatively charged DNA phosphate backbone, whereas in a transcriptionally active state (right nucleosome), lysine residues are modified by acetyl groups that neutralize a lysine’s positive charge. Transcriptional coactivators such as cyclic adenosine monophosphate response element–binding protein (CBP) are histone acetyltransferases that acetylate lysine residues on histone N-terminal tails. This acetylated state correlates with transcriptional activation. The opposing activity is carried out by HDACs, which remove acetyl groups from lysine residues, correlating with transcriptional silencing. Competitive inhibitors of HDACs (eg, trichostatin A [TSA], suberoylanilide hydroxamic acid [SAHA], sodium butyrate [NaBut], and valproic acid [VPA]) directly interact with and prevent HDACs from deacetylating lysines, thus inducing a hyperacetylated and transcriptionally active state

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