The central research goal of this new program project application is to determine the extent of genetic correlation of sensitivity, tolerance, and withdrawal for several effects of ethanol (EtOH) in mice. Several responses reflecting EtOH's hedonic, sedative, endocrine, and withdrawal effects will be analyzed using behavioral, neuropharmacologically specified mice after acute EtOH to determine the genetic bases for initial sensitivity to EtOH. They will also be studied after repeated administrations of EtOH using different responses and patterns of exposure. The rates of onset and maximal degree of tolerance or sensitization achieved will be estimated. Two methods will be employed to estimate the presence of genetic correlations. First, all component projects will study acute and/or chronic EtOH effects in a battery of 20 Recombinant Inbred (RI) strains, derived from the parental inbred strains C57BL/6J (C57) and DBA/2J (DBA). Common use of this panel of RI strains by all projects will offer several advantages. All projects will be contributing to a central data base which will offer much more information than if similar studies were carried out independently. It will also be possible to detect any potential single gene difference in this data set, and existing indications of single gene differences in the BXD RI panel described above may be followed up in the proposed research. The second method to be employed to estimate genetic correlations will be to study the divergence of selectively bred mouse lines for the presence of correlated responses. Lines selected for three different responses to EtOH (WSP/WSR, HOT/COLD, FAST/SLOW) will be studied. Individual projects will assess one or more of these selected lines to provide convergent validity of any genetic correlations assessed in the BXD RI panel.
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