To date, existing genetic animal models do not self-administer alcohol uncontrollably. The present proposal will use a combination of genetic and environmental manipulations to demonstrate excessive alcohol intake induced by withdrawal with the goal of producing an animal model that is easily exported to other laboratories within and beyond the INIA. The data will be made available to the Informatics Core of the INIA to suggest targets for molecular studies (Gene Array Core) as well as physiological studies (Neurocircuitry subgroup and Imaging Core). This project also will make extensive use of the Genetic Animal Models Core. Studies related to Specific Aim 1 will provide important information on the existence of genotypes with high ethanol consumption and whether these animals consume intoxicating doses of ethanol. Studies related to Specific Aim 2 will provide critical background information for an optimal paradigm to be used in the selective breeding aim (i.e., Specific Aim 3), the goal of which is to produce one or more reliable genetic animal model(s) of excessive drinking. The model should be genetically fairly stable at genes not important for the selection response (i.e., drift should be minimized) and replications of the experiment will be generated to eliminate false- positive estimates of genetic correlation. Since we are proposing to produce 2-3 independent replicate lines for excessive alcohol intake, any parallelism between the directly selected and correlated responses will offer very strong evidence for genetic codetermination of the phenotype. The studies related to Specific Aim 4 will give a clearer idea of the role of withdrawal-related and preference-related genes to the excessive alcohol intake phenotype, since additional genetic animal models as well as genotypes from other INIA sites will be tested. Collectively, the proposed studies will address a long term goal of our consortium which is to determine the neurobiological mechanisms underlying the excessive alcohol intake phenotype. Not only will this information help in furthering our understanding of the interaction between ethanol intake and withdrawal, but it also would aid in the development of new strategies for the treatment of alcoholism.
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