Genetic analysis of rapid tolerance to ethanol's incoordinating effects in mice: inbred strains and artificial selection.
Ethanol tolerance, a decrease in drug responsiveness with repeated administrations, is an important diagnostic criterion for alcoholism. Rapid tolerance develops within 8-24 hours of an initial ethanol exposure and shares many similarities with chronic tolerance. The genetic contribution to rapid tolerance to ethanol-induced ataxia was estimated using a panel of inbred strains of mice. Strains differed significantly in the degree of rapid tolerance development, which had a broad-sense heritability estimate of 0.11. Artificial selection was carried out to develop lines of mice that would show High (HRT) and Low (LRT) levels of Rapid Tolerance. Starting with HS/Npt mice, derived from a systematic cross of eight inbred strains, a significant response to selection was seen in replicate 1 by the third selection generation. No difference was found in replicate 2. Heritability estimates after the fourth generation were 0.25 for HRT-1 mice and 0.06 for LRT-1 mice. HRT-1 and LRT-1 mice also differed significantly in chronic tolerance development to four doses of ethanol. These studies provide evidence for a genetic contribution to rapid tolerance and support a genetic link between rapid and chronic tolerance to ethanol's ataxic effects.
Rustay
Nathan R
NR
Portland Alcohol Research Center, Department of Behavioral Neuroscience, Oregon Health & Science University, and Department of Veterans Affairs Medical Center, Portland, Oregon 97239 USA. rustayn@mail.nih.gov
Crabbe
John C
JC
D000818:Animals; D004361:Drug Tolerance / Q000235:genetics*; D000431:Ethanol / Q000097:blood; D005260:Female; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics*; D012641:Selection, Genetic
D000431:Ethanol