Quantitative trait loci mapping of genes that influence the sensitivity and tolerance to ethanol-induced hypothermia in BXD recombinant inbred mice

J. C. Crabbe, J. K. Belknap, S. R. Mitchell, L. I. Crawshaw

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

A recent method allows the identification of the rough genetic map location in mice of genes that exert modest affects on continuously distributed (i.e., quantitative) variables. Sensitivity and tolerance to the hypothermic effect of ethanol were studied with the purpose of identifying such quantitative trait loci (QTL). Mice from two progenitor inbred strains, C57BL/6J and DBA/2J and 19 of their recombinant inbred (RI) BXD strains, were given ethanol daily for 3 days. By administering several doses of ethanol and recording multiple postdrug temperatures on the first and third injection day, the authors were able to compute several indices of initial sensitivity and tolerance magnitude in the RI strain battery. The strains differed at most times and doses in their acute reductions in body temperature with respect to their predrug base lines, which indicated genetic control of sensitivity to ethanol-induced hypothermia. The areas under the curve (which describes the initial hypothermic response over time), a measure that reflects both the maximal hypothermia achieved and the duration of total hypothermic response, also differed. The strains also differed in the magnitude of the tolerance developed to ethanol-induced hypothermia. Genetic determinants of sensitivity (and tolerance) to different doses of ethanol were primarily independent, although genetic sensitivity and tolerance to the intermediate (2- and 3-g/kg) doses were significantly correlated. A comparison of the pattern of strain means for their sensitivity and tolerance to ethanol-induced hypothermia with a data base that consisted of the genotype of each BXD RI strain for almost 800 mapped polymorphic genetic markers revealed associations with several potential QTL for sensitivity and several others for tolerance, which appeared on all mouse chromosomes. Some QTL were significantly associated with both sensitivity and tolerance, which indicated that a nearby gene influences both. QTL analyses also identified several chromosomal regions in which specific candidate genes of potential relevance are mapped.

Original languageEnglish (US)
Pages (from-to)184-192
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume269
Issue number1
StatePublished - Jan 1 1994

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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