Tolerance of ethanol can be simply defined as an acquired resistance to the effect of the drug, but it is a complex phenomenon. Acute, rapid and chronic functional ethanol tolerance have been described, and there is also an effect of learning on ethanol tolerance. Although both acute and chronic tolerance are postulated to predict or contribute to the development to the development of alcohol abuse/alcoholism, little is known about the mechanisms or determinants of the different forms of tolerance. To assess common genetic determinants of acute and chronic ethanol tolerance, we will measure chronic tolerance to the incoordinating /motor-impairing effects of ethanol (ED60 for loss of balance on a dowel rod and ED60 for loss of balance on a rotorod treadmill) and to the hypnotic effect of ethanol (ED60 for loss of righting reflex) in lines of mice that have been selectively bred for high and low acute functional tolerance to the incoordination effect of ethanol (HAFT and LAFT mice). Preliminary data suggests that HAFT mice develop greater chronic tolerance to the incoordinating and hypnotic effects of ethanol than LAFT mice, and if chronic tolerance represents a correlated response to selection in these lines, the results will suggest that common genes influence acute and chronic ethanol tolerance. We will also evaluate acute tolerance to the anxiolytic effect of ethanol, a negative reinforcing effect, in HAFT and LAFT mice, and will determine changes in acute tolerance to this effect of ethanol in HAFT and LAFT mice treated chronically with ethanol. Tolerance to the anxiolytic action of ethanol is postulated to be important in modulating ethanol consumption. All of our studies will measure the development of """"""""environment-dependent"""""""" and """"""""environment- independent"""""""" chronic tolerance, and will be carried out in replicate lines of mice over several generations of selection. We will also evaluate changes in expression of mRNA for GABAa receptor subunits, by in situ hybridization, in brains of chronically ethanol-tolerant HAFT and LAFT mice, compared to controls, to determine the association of these changes with chronic environment-dependent of environment-independent ethanol tolerance. Any changes correlated with the development or extent of either form of chronic tolerance in the two lines of mice will be verified by RPA and immunoblotting, and GABAa receptor function will also be measured. Determination of acute and chronic ethanol tolerance in the HAFT and LAFT mice will provide for a better understanding of ethanol tolerance as a multifaceted or singular phenomenon, and will pave the way for identification of the common genetic determinants of the various forms of tolerance.
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