Epigenetic Dysregulation in Alcohol-Associated Behaviors: Preclinical and Clinical Evidence

: Alcohol use disorder (AUD) is characterized by loss of control over intake and drinking despite harmful consequences. At a molecular level, AUD is associated with long-term neuroadaptations in key brain regions that are involved in reward processing and decision-making. Over the last decades, a great effort has been made to understand the neurobiological basis underlying AUD. Epigenetic mechanisms have emerged as an important mechanism in the regulation of long-term alcohol-induced gene expression changes. Here, we review the literature supporting a role for epigenetic processes in AUD. We particularly focused on the three most studied epigenetic mechanisms: DNA methylation, Histone modification and non-coding RNAs. Clinical studies indicate an association between AUD and DNA methylation both at the gene and global levels. Using behavioral paradigms that mimic some of the characteristics of AUD, preclinical studies demonstrate that changes in epigenetic mechanisms can functionally impact alcohol-associated behaviors. While many studies support a therapeutic potential for targeting epigenetic enzymes, more research is needed to fully understand their role in AUD. Identification of brain circuits underlying alcohol-associated behaviors has made major advances in recent years. However, there are very few studies that investigate how epigenetic mechanisms can affect these circuits or impact the neuronal ensembles that promote alcohol-associated behaviors. Studies that focus on the role of circuit-specific and cell-specific epigenetic changes for clinically relevant alcohol behaviors may provide new insights on the functional role of epigenetic processes in AUD.