The major objective of this new Research Component is to selectively breed replicate mouse lines for high and low alcohol preference (HAP and LAP) starting from the HS/Ibg heterogeneous stock. This breeding program will also include replicate control lines. Since the mouse genome is much better delineated than that of the rat, we hope that in the future the HAP and LAP mouse lines can facilitate the localization of genes relevant in determining alcohol drinking behavior. For the next five years, efforts will be devoted to the following: (1) selective breeding of the replicate HAP, LAP and control lines; (2) calculating the realized heritability for the divergent selection; (3) characterizing the alcohol drinking behaviors of the HAP and LAP replicate lines, e.g. pattern of alcohol drinking bouts, blood ethanol concentrations attainable with each drinking bout, elasticity of alcohol drinking when diet is manipulated, and development of conditioned taste aversion; and (4) determining the relationship of high and low alcohol preference to other alcohol-related traits, e.g. alcohol elimination rates, hepatic ADH and ALDH activities, stimulation of spontaneous motor activity with low-dose ethanol, initial sensitivity and rapid development of acute tolerance in response to high- dose ethanol, operant responding (e.g. head-poke or bar-pressing) to obtain alcohol, and brain contents of serotonin (5HT) and dopamine (DA) and their metabolites. Most of the methods to be used are already established in our Alcohol Research Center. Few new methods have to be adopted from other workers in the field and they should not constitute major obstacles. consultation help from Dr. Donald P. Doolittle (The Jackson Laboratory) and Dr. R. Thomas Gentry (VAMC, Bronx, NY) will facilitate many aspects of this new Research Component.
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