Elaine H Shen | Search PubMed

PubMed2003

Mapping quantitative trait loci mediating sensitivity to etomidate.

Long- and Short-Sleep (LS and SS) mice were selectively bred for differences in ethanol-induced loss of the righting reflex (LORR) and have been found to differ in LORR induced by various anesthetic agents. We used a two-stage mapping strategy to identify quantitative trait loci (QTLs) affecting duration of LORR caused by the general anesthetic etomidate and brain levels of etomidate (BEL) following regain of the righting reflex. Analysis of recombinant-inbred strains derived from a cross between LS and SS mice (LSXSS) yielded a heritability estimate of 0.23 for etomidate-induced LORR and identified one marker that showed suggestive linkage for a QTL, on mouse Chromosome (chr) 12. Mapping in an F(2) population derived from a cross between inbred LS and SS (ILS and ISS) revealed a significant QTL for etomidate-induced LORR on Chr 12, and two significant QTLs mediating BEL on Chrs 6 and 12. Several QTLs showing suggestive linkage for etomidate-induced LORR and BEL were also identified in the F(2) population. Brain levels of etomidate in the RI and F(2) mice suggested that differences in LORR were due to differential central nervous system sensitivity, rather than differential etomidate metabolism. Interestingly, the region on Chr 7 has also been identified as a region influencing ethanol-induced LORR, suggesting the possibility of a common genetic mechanism mediating etomidate and ethanol sensitivity. These QTL regions need to be further narrowed before the testing of candidate genes is feasible.

Analysis of Variance↗

PubMed2002

Forward, relaxed, and reverse selection for reduced and enhanced sensitivity to ethanol's locomotor stimulant effects in mice.

BACKGROUND: Rarely have trait markers for alcoholism risk been identified. However, relative sensitivity to the arousing effects of ethanol and sensitivity to ethanol's sedative effects have been distinguished as potentially valuable behavioral risk factors. Both traits are genetically influenced and have been modeled in mice by measuring sensitivity to ethanol-induced locomotor stimulation and hypnosis. Reverse selection was performed to examine the hypothesis that forward selection for differential sensitivity to ethanol's locomotor stimulant effects resulted in homozygous fixation of selection trait-relevant alleles and to test the hypothesis that common genes influence ethanol's stimulant and sedative effects. METHODS: Bidirectional selective breeding was completed for enhanced (FAST mice) and reduced (SLOW mice) sensitivity to ethanol's locomotor stimulant effects. Selection was terminated (relaxed), and the lines were tested to detect genetic drift. Reverse selection for enhanced sensitivity to ethanol-induced stimulation in SLOW mice and reduced sensitivity in FAST mice was performed for 16 generations. Forward and reverse selected lines were tested for sensitivity to ethanol's sedative effects by measuring duration of ethanol-induced loss of righting reflex. RESULTS: Differential sensitivity to the sedative effects of ethanol emerged with selection for differential ethanol stimulation, indicating a common genetic influence on these traits. SLOW mice developed greater sensitivity to ethanol's sedative effects relative to FAST mice. Reverse selection, never before reported for a pharmacogenetic trait, was effective in eliminating most of the difference in stimulant sensitivity between the FAST and SLOW lines and also eliminated the difference in loss of righting reflex duration. CONCLUSIONS: Residual heterozygosity persisted at trait-relevant loci even at the selection plateau, possibly due to heterosis, natural selection favoring heterozygosity, or epistatic phenomena involving differences in the sets of genes regulating the high- versus low-sensitivity traits. They also suggest that some common genes influence sensitivity to ethanol's locomotor stimulant and sedative effects.

Alcohol Drinking↗