Acute ethanol exposure stimulates brain reward pathways. Upon chronic exposure, neural adaptations occur which generate new and long lasting behaviors such as tolerance, sensitization, and craving. We, and others, have hypothesized that stepwise changes in gene expression are an important part of the molecular mechanisms underlying experience-dependent neural adaptations leading to ethanol addiction. Studies in humans and animals have shown that acute behavioral responses to ethanol have predictive value in terms of the risk for excessive ethanol consumption and alcoholism. Here we hypothesize that changes in brain gene expression occurring with acute ethanol are an important part of the interplay between acute behavioral responses to ethanol and the risks for abusive drinking behavior. We propose to use high-density oligonucleotide arrays to provide a non-biased and a near genomic-level analysis of gene expression in brain areas related to the mesolimbocortical dopamine reward pathway. Our laboratory has developed extensive experience in the use of high-density oligonucleotide arrays for the study of changes in brain gene expression resulting from exposure to drugs of abuse such as ethanol or cocaine. We will characterize the time course and dose response of expression changes occurring in four different brain regions following acute ethanol exposure. Results will be contrasted in two different inbred lines of mice, C57BL/6J (B6) and DBA/2J (D2), which have markedly divergent responses to acute ethanol and tendencies for ethanol consumption. A comprehensive data analysis approach will be utilized including multivariant studies such as hierarchical clustering and self-organizing maps, together with a high throughput mining of biological databases. The goal will be to identify clusters of genes with expression patterns correlating with the differing behavioral responses of B6 and D2 mice. Such expression patterns may identify cellular functions critical to the neurobiology of acute ethanol action. The second specific aim will study the pharmacology of expression changes occurring with acute ethanol. In particular, we will characterize whether agents known to alter acute ethanol behavioral responses and ethanol drinking behavior also modulate specific gene expression profiles correlated with acute ethanol actions. Finally, we will determine whether prior experience with ethanol, as seen with locomotor sensitization, alters expression profiles elicited by acute ethanol exposure. This will identify acute ethanol-induced expression patterns that are potentially important for long lasting neuroadaptive events occurring with repeated ethanol exposure. All of the data produced in these studies will be rapidly made available to other investigators through a web site we have already established for posting array results. Such information dissemination is crucial for the """"""""hypothesis generating"""""""" capacity of the massively parallel and non-biased observations generated by DNA arrays. In summary, this work will greatly increase our understanding of brain molecular responses to ethanol that are important for either acute behavioral responses or long-term maladaptive behaviors as seen in alcoholism. These findings might generate novel insights for the treatment of alcoholism.
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