Halothane sensitivity in replicate mouse lines selected for diazepam sensitivity or resistance.
We have previously shown that mice selected for sensitivity to diazepam are also more sensitive to halothane, and that halothane augments the gamma-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 GABAA 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).(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh, Pennsylvania.
J J
JJ
Quinlan
K
K
Jin
E J
EJ
Gallaher
A F
AF
McCrae
L L
LL
Firestone
D000818:Animals; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006221:Halothane / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011963:Receptors, GABA-A / Q000187:drug effects
D011963:Receptors, GABA-A; D003975:Diazepam; D006221:Halothane