Epigenetic Mechanisms in Drug Addiction



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Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies have begun to focus on the molecular mechanisms by which drugs of abuse, and related environmental stimuli, such as drug-associated associated cues or stress, converge on the genome to alter specific geneprograms. Increasing evidence suggests that these stable gene expression changes in neurons are mediatedin part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. Indeed, genome-wide analysis using chromatin immunoprecipitation coupled with promoter microarrays in vivo, identified on which genes chronic cocaine exposure alters histone acetylation and methylation in the nucleus accumbens, a key brain reward region. In addition to providing novel insight into basic transcriptional mechanisms co-opted by cocaine, these data revealed a new class of cocaine-regulated genes, the sirtuins, which potently regulate reward behavior. In order to further understand the mechanisms by which cocaine regulates chromatin structure, I investigated enzymes which control levels of histone acetylation, histone deacetylases (HDACs). Chronic, but not acute, exposure to cocaine decreased the function of a class II HDAC, HDAC5, in the NAc, which allows for increased histone acetylation and transcription of HDAC5 target genes. This regulation is behaviorally important, as loss of HDAC5 causes hypersensitive responses to chronic, but not acute, cocaine. I have also identified a key roleof the class I HDAC, HDAC1, which interacts with the drug-induced transcription factor, ΔFosB, to repress c-fos gene induction in striatum after chronic psychostimulant exposure. Taken together, these findings suggest that proper balance of histone acetylation in the NAc is a crucial factor in the saliency of cocaine action, and that disruption of this balance may be involved in the transition from acuteadaptive responses to chronic psychiatric illness.

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