Epigenetic regulation in drug addiction

The interaction between environmental signals and genes has now taken on a clear molecular form as demonstrated by stable changes in chromatin structure. These changes occur through activation or repression of specific gene programmes by a combination of chromatin remodelling, activation and enzymatic modification of DNA and histones as well as nucleosomal subunit exchange. Recent research investigating the molecular mechanisms controlling drug-induced transcriptional, behavioural and synaptic activity has shown a direct role for chromatin remodelling – termed as epigenetic regulation – of neuronal gene programmes and subsequent addictive behaviour arising from it. Recent data suggest that repeated exposure to certain drugs promotes changes in levels of histone acetylation, phosphorylation and methylation, together with alterations in DNA methylation levels in the neurons of the brain reward centre, localised in the Nucleus Accumbens (NAc) region of the limbic system. The combination of acetylating, phosphorylating and methylating H3 and H4 histone tails alter chromatin compaction thereby promoting altered levels of cellular gene expression. Histone modifications, which weaken histone interaction with DNA or that promote recruitment of transcriptional activating complexes, correlate with permissive gene expression. Histone deacetylation, (which strengthen histone: DNA contacts), or histone methylation, (which recruits repressive complexes to chromatin), promote a state of transcriptional repression. Using animal models, acute cocaine treatment increases H4 acetylation at acutely regulated gene promoters, whereas H3 acetylation appears to predominate at chronically induced promoters. Chronic cocaine and alcohol treatment activate and repress many genes such as FosB, Cdk5, and Bdnf, where their dysregulation, at the chromatin level, contribute to the development and maintenance of addiction. Following drug exposure, it is still unknown, howver, how long these changes in chromatin structure persist in affecting neuronal function, but some do so for life