Dispositional without functional tolerance to the hypothermic effects of pentobarbital in the rat
Commissaris, R.L.; Semeyn, D.R.; Rech, R.H.
Journal of Pharmacology and Experimental Therapeutics 220(3): 536-539
1982
ISSN/ISBN: 0022-3565 PMID: 7062264 Document Number: 189631
The nature of the tolerance developed to the hypothermic effects of pentobarbital (PB) after short-term chronic administratiln of this agent was determined in female rats. Rectal temperature was determined in animals maintained on either a chronic PB or control regimen. The chronic PB treatment consisted of 6 days of twice-daily i.p. injections (30 mg/kg each) of PB plus ad lib feeding of ground chow containing 2.0 mg PB/g. Controls were administered ground chow and saline injections. After 7 days, control animals manifested a dose-dependent decrease in body temperature after various i.p. test doess (10, 14.2, 20, 28.4 and 40 mg/kg) of PB. Subjects receiving chronic PB administration showed an attenuation of the hypothermic effect, as indicated by a significant shift to the right in the dose-response curve for the test doses in this group. Gas chromatographic analysis of plasma levels in these 2 groups after i.p. administration of 20 mg/kg of PB resulted in T1/2 [half-life] values of 150 and 18 min for control and chronic PB-treated subjects, respectively. Chronic PB treatment enhances its own metabolism. Regression analysis of the change in body temperature vs. the log of the brain PB concentration (as determined by gas chromatography) resulted in highly significant correlations for both chronic PB-treated and control subjects, and these regression lines did not differ from one another. Evidently, chronic PB administration over a 1-wk period results in pronounced tolerance to the hypothermic effects of this agent, and this tolerance appears to be entirely dispositional in nature. The latter conclusion is supported by the decrease in the plasma T1/2 values for PB in the chronically-treated group and the lack of difference in hypothermic responses between the groups at equivalent brain concentrations of PB.