Rapid tolerance to rotarod ataxia has previously been demonstrated in mice after sequential ethanol injections. Here we tested DBA/2J and C57BL/6J mice for initial ethanol sensitivity; DBA/2J mice were more sensitive (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 blood ethanol concentrations at the recovery from ataxia over five sequential injections; tolerance reached a plateau in about 5 hr. DBA/2J mice became very tolerant (final ethanol threshold 3.47 +/- 0.16 mg/ml, an increase of 3.07 mg/ml, or 8.7-fold above base line); B6 became slightly tolerant (final ethanol threshold 2.62 +/- 12 mg/ml, and increase of 1.18, or 1.8-fold above base line). Therefore, by the end of the treatment regimen, the rank order of sensitivity of the two strains had reversed. We then tested 25 recombinant inbred strains from among strains representing a cross between C57BL/6J and DBA/2J inbred strains, followed by a quantitative trait locus analysis with a database of 1522 markers to identify provisional loci. This procedure identified 19 markers on 11 chromosomes for initial sensitivity, 18 markers on 9 chromosomes for tolerance (delta) and 21 markers on 11 chromosomes for tolerance (fold-increase). Of these, 17 markers were in common, which suggests that initial sensitivity and tolerance share substantial genetic codetermination. Major candidate loci will be confirmed by genotyping B6D2F2 offspring that have been tested for initial sensitivity and tolerance.