Epigenetic Mechanisms of Alcohol Neuroadaptation: Insights from Drosophila.

Abstract

Alcohol addiction is a serious condition perpetuated by enduring physiological and behavioral adaptations. An important component of these adaptations is the long-term rearrangement of neuronal gene expression in the brain of the addicted individual. Epigenetic histone modifications have recently surfaced as important modulators of the transcriptional adaptation to alcohol as these are thought to represent a form of transcriptional memory that is directly imprinted on the chromosome. Some histone modifications affect transcription by modulating the accessibility of the underlying DNA, whereas others have been proposed to serve as marks read by transcription factors as a "histone code" that helps to specify the expression level of a gene. Although the effects of some epigenetic modifications on the transcriptional activity of genes are well known, the mechanisms by which alcohol consumption produces this rearrangement and leads to lasting changes in behavior remain unresolved. Recent advances using the Drosophila model system have started to unravel the epigenetic modulators underlying functional alcohol neuroadaptations. In this review, we discuss the role of 3 different histone modification systems in Drosophila, which have a direct impact on key alcohol neuroadaptations associated with the addictive process. These systems involve the histone deacetylase Sirt1, the histone acetyltransferase CREB-binding protein (CBP), and a subset of the Drosophila JmjC-Domain histone demethylase family.