This proposal utilizes lines of rats that have been selected for differential initial sensitivity to ethanol. These lines will be used to discover which genes control the molecular mechanisms of action of ethanol in the brain. This information will be compared with similar data from mice and the results extrapolated to humans. Identification of genes responsible for the genetic risk of development of alcoholism is the ultimate goal of these studies. These rats, High Alcohol Sensitive, (HAS) and Low Alcohol Sensitive (LAS) and the control lines (CAS) have been selectively bred for 24 generations. The criteria for selection is """"""""sleep time"""""""" and blood ethanol at awakening following a standard dose of ethanol. There is essentially no overlap between blood ethanol at awakening between the HAS and LAS lines. Replicate lines, started from separate stocks of the N/Nih heterogeneous stock of rats, are maintained. A Quantitative Trait Loci project is underway and depends upon this proposal for the phenotypic testing of parents, F1 and F2 animals from a cross of both outbred lines and inbred strains. In the current proposal, we undertake to more closely define the actions of ethanol at the GABA receptor and the role of glutamate in the actions of ethanol. We will also investigate very rapid acute tolerance, acute functional tolerance and rapid tolerance. We will investigate the actions of dehydroepiandrosterone and its sulfate derivative on the metabolism and actions of ethanol. Other neurosteroids have been found to have differential effects on ethanol responses in these lines of rats.
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