The DNA methylation enzymatic machinery in substance use disorders: a systematic review

Substance use disorders (SUD) are chronic affections defined by similar symptoms across a variety of psychoactive drugs, including alcohol, cocaine, opioids, or methamphetamine. Epigenetic mechanisms such as DNA methylation represent key candidates to help explain the long-lasting effect of these drugs, as well as inter-individual variation in vulnerability. Here, we systematically reviewed current knowledge on the role of DNA methylation and the related enzymatic machinery in rodent models of SUD. Using a prospectively registered methodology, 99 articles were prioritized. A first set of studies manipulated the expression or activity of methylation or demethylation pathways. Depending on the brain region or drug considered, SUD-related behavioral and molecular manifestations were bidirectionally modulated, suggesting both pathogenic and protective roles for drug-induced methylomic plasticity. A second set of articles focused on candidate genes. Although significant heterogeneity across experimental models, brain regions or gene targets resulted in an absence of replicated findings, available data nevertheless support the notion that drugs of abuse trigger DNA methylation changes at discrete loci. Third, recent genome-wide studies have started to demonstrate that these drugs recruit widespread reprogramming. Strikingly, most adaptations occur outside promoter regions, highlighting an important challenge toward their functional interpretation. Finally, studies of drug exposure during gestation or adolescence suggest long-lasting consequences, with the potential for early intervention.