The proposed study will evaluate the neurobiological consequences of prolonged ethanol drinking. Such studies will identify the regions of the brain that are sensitive to ethanol and potentially help to focus treatment strategies to combat abuse and the neurologic complications of chronic alcoholism. It is known that the magnitude and topography of ethanol's effects on brain function are modified by long-term ethanol exposure. Human studies are limited, however, by the spatial resolution of current methods and the various confounds associated with human research on alcoholism. Animal studies are needed, therefore, to directly link ethanol drinking to changes in brain function within specific sites. To date, imaging studies of ethanol's effects in the brains of animals have used methods that were specifically designed to identify the regional pattern of brain function within a small time window. Accordingly, they have been very useful in defining, the response to acute ethanol intake or acute withdrawal. These methods are, however, less well equipped to evaluate long-term changes in brain function which are modified over a period of hours to weeks. It is not sensitive to short-lived phenomena such as acute ethanol intake and withdrawal. Furthermore, quantitative methods have been recently devised. Therefore, the present proposal will first establish the quantitative method of assessing cytochrome oxidase histochemistry in this laboratory. These procedures involve the use of internal standards and quantitative densitometry. Next, the consequences of ethanol self- administration in rodents will be assessed using this method. This effort will serve as an initial evaluation of the long-term effects of ethanol intake. A self-administration paradigm was specifically chosen to most closely model human alcohol drinking. The use of the CO method will be particularly useful because it avoids confounds associated with acute alcohol intake or withdrawal. There are clear indications that changes in brain function result from chronic alcohol intake in humans and animals; this approach is likely to identify key sites that manifest long-term changes associated with ethanol drinking.
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