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Halothane Sensitivity in Replicate Mouse Lines Selected for Diazepam Sensitivity or Resistance

Joseph J. Quinlan, MD^*, Kun Jin, PhD, Edward J. Gallaher, PhD, Anne F. McCrae, MB, ChB, FFARCSI, and Leonard L. Firestone, MD^*

*Department of Anesthesiology and Critical Care Medicine Department of Clinical Epidemiology and Family Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania Medical Research Service, Veteran's Administration Medical Center, Portland, Oregon Department of Anaesthesia, Royal Infirmary of Edinburgh, Edinburgh, Scotland

Abstract

We have previously shown that mice selected for sensitivity to diazepam are also more sensitive to halothane, and that halothane augments the -aminobutyric acid (GABA)-mediated chloride flux response in brain tissue from diazepam-sensitive (DS) mice to a greater degree than in diazepam-resistant (DR) mice. These findings suggest that the GABA_A receptor is an important site of halothane action. To confirm this correlation, halothane requirement was determined in two independently developed replicate lines of DS and DR mice. Association of the traits of diazepam and halothane sensitivity in replicate lines of DS mice diminishes the probability that the original finding was due to a false-positive correlation, and instead suggests that it results from the common action of genes controlling diazepam sensitivity. Halothane median effective concentration (EC50) was determined by using the end-point of loss of righting reflex in two replicate lines of mice selected for diazepam sensitivity (resistant mice = diazepam high performance-1 and –2 [DHP-1 and DHP-2], sensitive mice = diazepam low performance-1 and –2 [DLP-1 and DLP-2]). DLP-1 and DLP-2 mice were sensitive to halothane, whereas DHP-1 and DHP-2 mice were resistant to halothane. Halothane EC₅₀ in the DLP-1 and DHP-1 mice was 0.86 ± 0.01 (se) and 1.10 ± 0.04 atm%, respectively (P < 0.0001), and that in the DLP-2 and DHP-2 mice was 0.88 ± 0.01 and 0.97 ± 0.02 atm%, respectively (P < 0.0001). Simultaneous analysis of the halothane concentration-response data from these replicate lines, and from the original DS/DR lines, using the likelihood inference method with a single slope parameter, yielded a rank order of halothane EC₅₀ values:

The probability that this rank order in halothane sensitivities is due to merely random effects (such as inbreeding or genetic drift) is 0.067. Since the probability is low that trait-irrelevant genes randomly co-segregated during multiple independent selection processes, a true correlation between the traits of diazepam and halothane sensitivity is highly likely. Thus a common mechanism may underlie these traits, strengthening the hypothesis that the GABA_A receptor is important in mediating the obtunding action of halothane.

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