The effects of chronic ethanol self-administration on global gene expression in the brain have not been extensively characterized. The majority of studies to examine brain gene expression have used rodent models, neuronal cells in culture, or tissue from archived human autopsy samples. While these studies have provided a wealth of information, the use of each of these model systems has limitations. The present study proposes to initiate a systematic analysis of ethanol-sensitive gene expression in relevant brain regions by starting with a brain region known to be affected by chronic ethanol consumption - the cerebellum. Although cerebellar involvement in movement related behaviors is well documented, there is a growing interest understanding the role of the cerebellum in the cognitive changes that occur in alcoholism. To investigate this question, this study will use a very unique and robust nonhuman primate model of chronic ethanol self administration developed at Wake Forest University. These experiments will be conducted with brain tissue from cynomolgus monkeys who have self-administered ethanol for 18 consecutive months at chronic levels (up to 4.0 g/kg/day). The advantages of using this model to investigate brain gene expression are threefold: (1) the close similarity of non-human primate to humans in terms of physiology, genetics, and consumption render it a very relevant model; (2) the entire (chronic) drinking history for these animals is known and; (3) the availability of tools (high density gene arrays) that permit the evaluation of whole-genome gene expression provide the possibility to achieve a level of gene expression analysis never before possible. The gene expression data generated from a within-subject design (examining three separate regions of the cerebellum in each animal), as well as a between-group design (comparison between chronic alcohol and alcoholna'fve; comparison between males and females) will provide significant new information. Identifying the molecular basis of neuropathology in the nonhuman primate brain resulting from chronic ethanol self-administration should have direct relevance to better understanding human alcoholism.

R21AA014984

2005-04-20

2008-03-31