IDENTIFICATION OF GENETIC-MARKERS FOR INITIAL SENSITIVITY AND RAPID TOLERANCE TO ETHANOL-INDUCED ATAXIA USING QUANTITATIVE TRAIT LOCUS ANALYSIS IN BXD RECOMBINANT INBRED MICE

Rapid tolerance to rotarod ataxia has previously been demonstrated in mice after sequential ethanol injections. Here we tested DBA/2J and C5 7BL/6J mice for initial ethanol sensitivity; DBA/2J mice were more sen sitive (0.40 +/- 0.17 mg/g brain) than C57BL/6J mice (1.44 +/- 0.12 mg /g). We then monitored the development of tolerance by quantifying blo od ethanol concentrations at the recovery from ataxia over five sequen tial injections; tolerance reached a plateau in about 5 hr, DBA/2J mic e became very tolerant (final ethanol threshold 3.47 +/- 0.16 mg/ml, a n increase of 3.07 mg/ml, or 8.7-fold above base line); B6 became slig htly tolerant (final ethanol threshold 2.62 +/- 12 mg/ml, an increase of 1.18, or 1.8-fold above base line). Therefore, by the end of the tr eatment regimen, the rank order of sensitivity of the two strains had reversed. We then tested 25 recombinant inbred strains from among stra ins representing a cross between C57BL/6J and DBA/2J inbred strains, f ollowed by a quantitative trait locus analysis with a database of 1522 markers to identify provisional loci. This procedure identified 19 ma rkers on 11 chromosomes for initial sensitivity, 18 markers on 9 chrom osomes for tolerance (delta) and 21 markers on 11 chromosomes for tole rance (fold-increase). Of these, 17 markers were in common, which sugg ests that initial sensitivity and tolerance share substantial genetic codetermination. Major candidate loci will be confirmed by genotyping B6D2F2 off-spring that have been tested for initial sensitivity and to lerance.