Gabriella Becerra

Introduction. Alcohol Use Disorder (AUD) criteria is met by approximately 1/3 of adults in the United States at some point in their lives.¹ AUD has been shown to be a heritable disease in family and twin studies and high levels of alcohol consumption change DNA methylation in central and peripheral tissues, indicating an epigenetic role in alcohol consumption and AUD.^2,3 DNA methylation occurs through different forms of the enzyme DNMT, including DNMT3A and DNMT3B, responsible for de novo methylation, and DNMT1, a maintenance methylator.⁴ Methods. Adolescent and adult rat models were used to replicate chronic alcohol use and adolescent binge drinking then DNMT activity and mRNA levels were quantified in nucleus accumbens and amygdala tissues using PCR, EpiQuik™ DNA methyltransferases activity/inhibition assay kit, and RNeasy Mini Kit.^4,5 The role of reactive oxygen species (ROS) in DMNT upregulation was investigated using an iron-overloaded mouse model and ethanol-treated neural precursor cells with NADPH oxidase inhibitors.^6,7 Additionally, alcohol and ROS production effects on GABAergic function were investigated using nucleus accumbens tissue harvested from an alcohol exposed rat model.⁸ Postmortem human brains were compared across AUD patients and unaffected controls to investigate differences in regulation of GABA subunits and neurosteroid biosynthetic enzymes.⁹ Results. Chronic and early alcohol exposed rats had differences in hypermethylation and DMNT activity and mRNA levels as well as decreased GABAergic function.^4,5,8 The changes in both DMNT and GABAergic function were directly connected to increases in ROS across the brains of alcohol exposed rats.^6,8 Hypermethylation of the 3α-HSD gene promoter was seen in AUD patients along with a decrease in mRNA expression of 3α-HSD. 3α-HSD is an important enzyme in the synthesis of neurosteroids which then potentiate GABAergic inhibition. A decrease in GABAAR α2 subunit was associated with increased methylation levels in the promoter in the AUD patients.⁹ Conclusions. GABAergic signaling has been shown to be involved in addiction and alcohol tolerance. Increased methylation of promoter regions of genes involved in the GABAergic pathway and their subsequent downregulation in the brain is connected with AUD, but these connections are not fully understood.⁹ Chronic and early drinking lead to increased methylation through generation of ROS.^4,5,7 Decreasing methylation activity in early and chronic drinkers may reverse disruption in GABAergic transmission and provide a therapeutic avenue for AUD. Additionally, increasing understanding of ROS generation from alcohol and its connection to DNMTs could increase treatment options for AUD.

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