The wealth of gene expression data accumulated during the past decade has generated long lists of candidate genes predisposing to excessive ethanol drinking or responding to ethanol exposure or withdrawal. The vast majority of these genes, however, are still awaiting functional validation. Numerous studies using genetically engineered mice and virus-mediated gene silencing or overexpression have assessed the influence of individual genes on ethanol self-administration [90-99]. The next challenge will be to hinder or replicate the coordinated changes in gene expression produced by ethanol dependence and examine the effect of this global transcriptional remodeling on ethanol drinking. Realization of this ambitious goal will necessitate identifying the molecular mechanisms orchestrating these coordinated changes. Potential “master switches” have emerged from recent studies in the form of transcription factors, miRNAs and chromatin-modifying enzymes, as detailed in sections above and summarized in Fig. (2). It will be critical to expand these mechanistic approaches in the future, in the hope of identifying novel targets whose pharmacological modulation could address the complexity of molecular adaptations associated with alcoholism and could ultimately be used for therapeutic purposes.
