Esra Gumuser

Introduction. Alcohol Use Disorder affects the United States both economically, with excessive binge drinking costing the U.S. $249 billion in 2010 alone¹, and in mortality, being responsible for over 30,000 deaths in the 2014².  Long-term alcohol use is known to affect nearly every organ system primarily through epigenetic remodeling entailing histone modifications that either promote (euchromatin) or reduce (heterochromatin) gene expression.  For instance, chronic alcohol exposure was found to promote a heterochromatin pattern of histone modification that reduces gene expression of a thiamin transporter in pancreatic acinar cells, promoting irreversible cell injury³. In the liver, alcohol exposure promoted the euchromatin pattern of histone modification to increase expression of alcohol dehydrogenase I enzyme promoting its metabolism⁴.  Clinically treated as a psychiatric illness, alcoholism is attributed to the dysregulation of the dopaminergic mesolimbic pathway involved in reward, motivation learning, and reinforcement. Methods. Recent studies using the animal model have delved into the role of epigenetic remodeling within the dysregulation of the mesolimbic pathway, in the context of adolescent binge drinking⁵. Results. Adolescent-intermittent ethanol (AIE) exposure rats were found to have significant reduction in Ki-67 cells, with this reduction of neurogenesis being restored with the administration of histone deactylases (HDAC) inhibitor. Furthermore, withdrawal from ethanol in AIE mice resulted in increased levels of HDAC activity, with the subsequent anxiety-like behavior persisting into adulthood⁶. Further studies found that HDAC activity was responsible for the development of tolerance, requiring increased intake of alcohol for desired anxiolytic effects⁷.  Conclusions. These animal models raise the question of the role of histone acetylation in being responsible for the dysregulation of neuronal pathways in alcoholism. However, animal models only capture a fraction of underlying molecular and phenotypic variability, considering that alcoholism is a multifactorial disorder with a very complex phenotype. Recent studies of brain slices of individuals with substance abuse related cause of death has allowed for the opportunity to describe epigenetic processes and their specific connection with gene expression profiles⁸. Research that employs a systems based approach in integrating epigenetics with transcription expression will allow researchers to prioritize dysregulated genes for follow-up studies, with the potential to identify novel drug-responsive networks.

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