The regulation of neuronal gene expression by alcohol

In recent years there has been an explosion of interest in how genes regulate alcohol drinking and contribute to alcoholism. This work has been stimulated by the completion of the human and mouse genome projects and the resulting availability of gene microarrays. Most of this work has been performed in drinking animals, and has utilized the extensive genetic variation among different mouse strains. At the same time, a much smaller amount of effort has gone into the in vitro study of the mechanisms underlying the regulation of individual genes by alcohol. These studies at the cellular and sub-cellular level are beginning to reveal the ways in which alcohol can interact with the transcriptional, translational and post-translational events inside the cell. Detailed studies of the promoter regions within several individual alcohol-responsive genes (ARGs) have been performed and this work has uncovered intricate signaling pathways that may be generalized to larger groups of ARGs. In the last few years several distinct ARGs have been identified from 35,000 mouse genes, by both the "top-down" approach (ex vivo gene arrays) and the "bottom-up" methods (in vitro promoter analysis). These divergent methodologies have converged on a surprisingly small number of genes encoding ion channels, receptors, transcription factors and proteins involved in synaptic function and remodeling. In this review we will describe some of the most interesting cellular and microarray work in the field, and will outline specific examples of genes for which the mechanisms of regulation by alcohol are now somewhat understood.