HALOTHANE SENSITIVITY IN REPLICATE MOUSE LINES SELECTED FOR DIAZEPAM SENSITIVITY OR RESISTANCE

We have previously shown that mice selected for sensitivity to diazepa m are also more sensitive to halothane, and that halothane augments th e gamma-aminobutyric acid (GABA)-mediated chloride flux response in br ain 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 trait s of diazepam and halothane sensitivity in replicate lines of DS mice diminishes the probability that the original finding was due to a fals e-positive correlation, and instead suggests that it results from the common actino of genes controlling diazepam sensitivity. Halothane med ian effective concentration (EC(50)) was determined by using the end-p oint of loss of righting reflex in two replicate lines of mice selecte d 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 h alothane, whereas DHP-1 and DHP-2 mice were resistant to halothane. Ha lothane 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 mcie was 0.88 +/- 0.01 and 0.97 +/- 0.02 atm%, respectively (P < 0.0001). Simultaneous analysis of the halothane concentration-respon se data from these replicat lines, and from the original DS/DR lines, using the likelihood inference method with a single slope paramet, yie lded a rank order of halothane EC(50) values: ($$) over tilde EC(50DHP -1) greater than or equal to ($$) over tilde EC(50DHP-2) > ($$) over t ilde EC(50DR) greater than or equal to ($$) over tilde EC(50DLP-1) > ( $$) over tilde EC(50DLP-2) greater than or equal to ($$) over tilde EC (50DS). The probability that this rank order in halothane sensitivitie s is due to merely random effects (such as inbreeding or genetic drift ) is 0.067. Since the probability is low that trait-irrelevant genes r andomly co-segregated during multiple independent selection processes, a true correlation between the traits of diazepam and halothane sensi tivity is highly likely. Thus a common mechanism may underlie these tr aits, strengthening the hypothesis that the GABA(A) receptor is import ant in mediating the obtunding action of halothane.