Epigenetics of drug addiction: a therapeutic opportunity and a transgenerational inheritance concern

Drug addiction has been defined as a chronic and relapsing brain disease, characterized by compulsive drug seeking and repeated use, despite harmful consequences. It involves substantial molecular, synaptic, and neurocircuitry neuroadaptations, that persist beyond acute abstinence and trigger relapses and deficits in cognitive function that stimulate compulsive consumption. Such long lasting effects cannot be explained on the basis of protein turnover and posttranslational modifications, which are relatively stable, but only last a matter of weeks. On the other hand, epigenetic remodelling and regulation of chromatin, allows for potent and precise activity-dependent control over gene expression, and contribute to the molecular mechanisms required for neuronal changes leading to long-lasting changes in behavior. Epigenetic mechanisms, including DNA methylation, histone post-translational modifications, chromatin remodeling and regulation mediated by non-coding RNAs have been demonstrated for several psychotropic substances, namely alcohol, heroin, cocaine, amphetamines, and cannabinoids.

Epigenetic modifications can be dynamically regulated by sets of enzymes that serve as ‘writers’ or ‘erasers’ to add or remove specific epigenetic marks, respectively, and by ‘readers’ that bind to these modifications and serve as effectors. Thus, a good understanding of such molecular mechanisms provides a new window of opportunity for the development of new therapeutic approaches in drug addiction.

Another point for due consideration is the hereditary nature of epigenetic effects. The epigenetic signature is normally erased in gametes and reset after fertilization, likely to prevent wide genome-wide epigenetic inheritance. However, a small number of genes undergo “imprinting,” whereby one copy of a gene and its nearby histones are methylated, leading to a permanent state of inactivation, which enables them to maintain their parent-of-origin methylation state. This mechanism of epigenetic transgenerational inheritance may provide a link between paternal drug exposure and addiction susceptibility in the offspring.