This project proposes to continue the selective breeding program, designed to develop lines of rats, expressing sensitivity and resistance to the acute central nervous system depressant effects of ethanol. The animal model produced will aid further in elucidation of the mechanism by which alcohol depresses the central nervous system, as well as provide a tool for studying how gene action mediates the response to alcohol effects. These studies may serve further in understanding the biological factors contributing to human alcoholism. Rats, originating from a large genetically heterogeneous base population, are being selected to have either prolonged or shortened """"""""sleep times"""""""" (i.e., duration of loss of the righting response) following a standard intraperitoneal dose of alcohol. Six lines, with two replicates in each direction, are maintained, two high sensitivity (long sleep), two low sensitivity (short sleep) and two control (unselected) lines. The relative effects of ethanol metabolism are assessed by measurement of blood alcohol levels upon recovery of the righting response. Within family selection is used and a minimum of ten families per line are maintained. Periodic monitoring of the lines as selection proceeds is being done to measure ethanol effects on related electrophysiological and biochemical phenotypes to determine the extent of genetic correlation of the behavioral response with these phenotypes. The species generality of these correlation studies are determined by comparison with the ethanol responses in the mouse model. Eventually, after maximum genetic response in both directions has been obtained (empirically, this has been found to be at least 20 generations of selection) inbred and recombinant inbred lines will be developed from the selected rat lines.
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