Jonathan Artz

 Background.  Repeated alcohol use results in altered gene expression responsible for the pathological neurobiological and behavioral changes associated with Alcohol Use Disorder (AUD).⁵ Strong cravings for alcohol, loss of self-control, development of physical dependence, and an increased tolerance for alcohol are some of the behaviors associated with AUD.⁷ Neuronal epigenetic modifications have been indicated as a cause of these behaviors⁵ Epigenetic modifications are changes in gene expression that occur without direct changes to the DNA sequence. They can occur through a variety of different mechanisms such as acetylation, methylation, and phosphorylation of DNA or histone proteins which ultimately result in increased or decreased protein production.⁵ Chronic alcohol use specifically results in histone H3 acetylation, methylation, and suppression of phosphorylation, all of which have been indicated as causes for some of the pathological changes seen in AUD.⁵ Given the role that these modifications play in AUD, treatments targeting alcohol induced epigenetic modifications offer a promising route for potential therapeutic intervention. Methods.  The standard models to study alcohol induced epigenetic changes are Sprague Dawley rats^3,4 and C57BL/6J mice⁶. The rodents were housed under traditional laboratory conditions and sorted into experimental and control groups. The animals in the experimental groups were exposed to alcohol via intraperitoneal injection,⁴ the Majchrowicz protocol,³ or a more standard free choice drinking protocol.^1,6 The rodents were then observed to study alcohol induced behavioral changes⁴ or sacrificed so that post-mortem analysis (primarily immunohistochemistry) could be done to observe the epigenetic changes that had occurred in the rodent brain tissue.^1,3,4,6 Results.  Alcohol exposure results in suppression of histone H3 phosphorylation, leading to a reduction in expression of the neuronal activity marker c-fos.³ Additionally, repeated alcohol consumption results in acetylation of histone H3, a modification that leads to pathogenic changes in expression brain development genes such as Bdnf and activity-regulated cytoskeleton-associated protein in the hippocampus and amygdala,^3,4 as well as increased anxiety-like and alcohol seeking behavior into adulthood if consumed during adolescence.⁴ Finally, inhibition of DNA methylation has been shown to reduce drinking behavior.²  Conclusions.  Ethanol exposure, particularly early in life, can result in disruptions in brain development through modifications to histone H3. These disruptions have been implicated as mechanisms through which behavior characteristic of AUD develop and represent promising avenues for future therapeutics. In fact, the quinolone compound, S4 has already been shown to reduce alcohol intake in a dose dependent manner through reversion of alcohol induced histone H3 modifications.¹

1.  Banerjee TS, Hazra A, Mondal NB, Das S. The quinoline compound, S4 effectively antagonizes alcohol intake in mice: Possible association with the histone H3 modifications. Neurochemistry international. 2015;87:117-27.
2. Mahnke A.H., Miranda R.C. & Homanics G.E., Epigenetic mediators and consequences of excessive alcohol consumption, Alcohol (2017), doi: 10.1016/j.alcohol.2017.02.357
3. Mcclain JA, Nixon K. Alcohol Induces Parallel Changes in Hippocampal Histone H3 Phosphorylation and c-Fos Protein Expression in Male Rats. Alcohol Clin Exp Res. 2016;40(1):102-12.
4. Pandey SC, Sakharkar AJ, Tang L, Zhang H. Potential role of adolescent alcohol exposure-induced amygdaloid histone modifications in anxiety and alcohol intake during adulthood. Neurobiol Dis. 2015;82:607-19.
5. Ponomarev, Igor. Epigenetic Control of Gene Expression in the Alcoholic Brain. Alcohol Research: Current Reviews. 2013;35(1):69-76
6. Stragier E, Massart R, Salery M, et al. Ethanol-induced epigenetic regulations at the Bdnf gene in C57BL/6J mice. Mol Psychiatry. 2015;20(3):405-12.
7. World Health Organization. Global status report on alcohol and health 2014. World Health Organization.