GENETIC SELECTION AND CHARACTERIZATION OF MOUSE LINES FOR ACUTE FUNCTIONAL TOLERANCE TO ETHANOL

Rapid adaptation to central nervous system inhibitory effects of ethan ol is observed in animals and humans and this acute functional toleran ce (AFT) is influenced by genotype in rodents. Studies have been condu cted to identify neurochemical processes influencing AFT to ethanol, b ut little is known regarding genetic regulation of AFT or genetic infl uences on processes that mediate acquisition of AFT. Our study was des igned to develop, by selective breeding, lines of mice that differ in acquisition of AFT to ethanol; such mouse lines will be valuable in id entifying the neuroadaptive processes mediating AFT. AFT is defined as the difference in blood ethanol concentration (BEC) at regaining bala nce on a stationary dowel rod after two consecutive doses of ethanol, 1.75 followed by 2.0 g/kg. Starting with a genetically heterogeneous f oundation stock (HS/Ibg), seven generations of selective breeding has been completed for high (HAFT(1)), low (LAFT(1)), and control lines an d four generations have been completed for the replicate HAFT(2) and L AFT(2) lines. The lines do not differ in initial sensitivity to ethano l; however, the means for AFT scores differ by 2.3- and 4.3-fold for f emales and males, respectively (106.5 vs. 46.5 mg ethanol/dl blood) fo r females and 106.2 vs. 24.8 mg/dl for males). Frequency distributions for HAFT(1) and LAFT(1) show only modest overlap in AFT scores. The l ines differ in rates of acquisition of AFT, but not in rates of ethano l clearance. Heritabilities were 0.04 and 0.26 for HAFT(1) and LAFT(1) lines, respectively, indicating that the selection was asymmetrical. Evidence is provided indicating that practice during intoxication has little effect on acquisition of AFT in HAFT(1) and LAFT(1) lines.