Emerging Role of Epigenetic Mechanisms in Alcohol Addiction

Abstract

Alcohol use disorder (AUD) is a complex brain disorder with an array of persistent behavioral and neurochemical manifestations. Both genetic and environmental factors are known to contribute to the development of AUD, and recent studies on alcohol exposure and subsequent changes in gene expression suggest the importance of epigenetic mechanisms. In particular, histone modifications and DNA methylation have emerged as important regulators of gene expression and associated phenotypes of AUD. Given the therapeutic potential of epigenetic targets, this review aims to summarize the role of epigenetic regulation in our current understanding of AUD by evaluating known epigenetic signatures of brain regions critical to addictive behaviors in both animal and human studies throughout various stages of AUD. More specifically, the effects of acute and chronic alcohol exposure, tolerance, and postexposure withdrawal on epigenetically induced changes to gene expression and synaptic plasticity within key brain regions and the associated behavioral phenotypes have been discussed. Understanding the contribution of epigenetic regulation to crucial signaling pathways may prove vital for future development of novel biomarkers and treatment agents in ameliorating or preventing AUD.

Keywords: Alcoholism; Amygdala; Anxiety; DNA Methylation; Epigenetics; Histone Acetylation; Histone Methylation.

Fig. 1

Summary of alcohol-induced histone modifications (acetylation/methylation) in the amygdala of animal models. Within the amygdala, acute ethanol (EtOH) induces histone H3 and H4 acetylation secondary to inhibited histone deacetylase (HDAC) activity and increased expression of the histone acetyltransferase [CREB-binding protein (CBP)]. These changes remodel chromatin to a less condensed form that allows for transcription factors (TFs) to access genes, such as activated CREB and CBP binding, resulting in increased expression of CREB targets, such as neuropeptide Y (NPY), prodynorphin (PDYN), brain-derived neurotrophic factor (BDNF), and activity-regulated cytoskeleton-associated protein (Arc). These modifications and related gene products in the amygdala are known to reduce anxiety-like and drinking behaviors. Tolerance and chronic exposure to EtOH normalizes molecular signatures of the epigenome. Upon withdrawal or in the case of genetic predisposition to alcoholism, HDAC activity is increased, and the subsequent histone deacetylation condenses the chromatin and downregulates the CREB pathway. This result in increased anxiety-like and drinking behaviors, decreased H3 and H4 acetylation, and decreased CBP, NPY, BDNF, and Arc expression. Ethanol will then recover normal chromatin from these states.

Fig. 2

Hypothetical model indicating possible changes in DNA methylation after acute ethanol (EtOH), chronic ethanol exposure, and withdrawal upon cessation. Animal studies consistently report that acute ethanol exposure induces global DNA demethylation and presumably relaxed chromatin within various brain nuclei, altering transcription factors (TFs) access and associated gene expression. Chronic exposure in animal and human samples reportedly increases global DNA methylation in several brain regions and peripheral blood samples. Based on these findings and the role chromatin remodeling plays in anxiety and drinking behavior, we hypothesize that alcohol withdrawal results in especially hypermethylated DNA and presumably condensed chromatin as a consequence of dysregulated epigenetic mechanisms. It is possible that DNMT inhibitor treatment (Tx) or acute ethanol exposure may lead to relaxed chromatin architecture due to DNMT inhibition.

Fig. 3

Promising pharmacotherapy treatment of alcoholism and withdrawal include DNA methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors, and possibly histone methyltransferase (HMT) inhibitors. Current studies suggest these interventions often mimic the effects of ethanol (EtOH) by relaxing chromatin and modulating anxiolysis, synaptic plasticity, and drinking behaviors. They have been shown to alter epigenetic mechanisms, prevent alcohol-induced reactive oxygen species (ROS) in neurons, and increase synaptic plasticity within critical brain regions that regulate addiction and alcoholism, such as the nucleus accumbens (NAc) and the amygdala. Presumably as a result, numerous studies have shown that DNMT and HDAC inhibitors reduce alcohol-intake, anxiety-like behaviors, and binge-like drinking behaviors. HMT inhibitors are a promising yet currently unexplored treatment consideration in AUD.