ethanol. Second, nuclear localization of protein kinase A has great implications for changes in the regulation of gene expression. These kinds of changes may well underlie some of the chronic adaptive and sustained responses produced by ethanol in neurons and in the brain. It remains to be determined whether protein kinase translocation occurs in all neurons or is localized to specific neuronal populations in the brain, like the nucleus accumbens.

The long-term consequences of adaptive changes involve changes in gene expression, which probably underlie the development of complex abnormalities such as addiction and alcoholic neurologic disorders. Moreover, changes in gene expression may help to answer a puzzling question in alcohol research: How is it that short-term exposure to alcohol produces functional and metabolic changes whereas long-term exposure causes structural pathology and disease?

Because chronic exposure to ethanol produces changes in cellular and molecular function that require selective changes in gene expression, Michael Miles at the Gallo Center searched for evidence that specific kinds of genes are either ''turned on" or turned off" by ethanol. He has already identified a family of ethanol-responsive genes. In this slide, it is clear that there is a selective increase in gene expression for some genes, including several stress protein genes. In order to study the regulation of ethanol-responsive genes, Dr. Miles coupled the promoter from an ethanol responsive gene to a reporter enzyme, chloramphenicol acetyltransferase (CAT). Now, assays of CAT activity can be used to identify factors that confer ethanol sensitivity. This will take us a long way in determining important regulatory mechanisms that medicate ethanol sensitivity and designing new therapies specifically to prevent or reverse adverse responses.

So, in a few short years, investigators at the Gallo Center have moved from behavioral concepts such as tolerance and dependence to selective effects of ethanol on gene expression and the regulation of signal transduction mechanisms in the cell. Undoubtedly, these changes contribute to altered complex behaviors, such as addiction, and the development of alcoholic brain disorders, such as dementia. This should not be surprising since CNS responses are ultimately regulated by the genes that control neural cell function.

As we accumulate increasing evidence of a role for gene expression in responding to ethanol, and perhaps conferring vulnerability to alcoholism, we can exploit advances in complex organisms in which behaviors can be linked to gene expression more easily than in human beings. Here is a slide highlighting some ethanol-induced behaviors in one such preparation. Acute exposure to ethanol first produces incoordination, then hyperactivity, and finally drowsiness and sleep. After awakening, there is transient incoordination, followed by a complete recovery. Although these behaviors resemble the effects of alcohol in human beings, this preparation is not a mammal, it is a fruitfly. Ulrike Heberlein has developed a Drosophila genetics laboratory at the Gallo Center to identify genes that mediate ethanol responses and perhaps to identify candidate genes



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