Metabolic and functional aspects of tolerance to chlormethiazole and cross-tolerance to ethanol in the rat.

Adult male rats were used to study tolerance to, and physical dependence on, chlormethiazole and cross-tolerance to ethanol. In sleeping time studies, chlormethiazole was given orally at a daily dose rising progressively from 100 to 175 mg/kg over a period of 1 month. The tolerance that developed appeared to be due to altered disposition of the drug rather than to decreased sensitivity of the CNS. In agreement with this conclusion, there was only minimal cross-tolerance to ethanol, and no detectable withdrawal reaction. In studies with the moving belt test, the rats were given chlormethiazole subcutaneously in a total dose of 200 mg/kg daily for 69 days. This resulted in an equivocal manifestation of tolerance on the moving belt test and a small, but significant, tolerance to the hypothermic effect of chlormethiazole. Only an equivocal manifestation of physical dependence was found. These findings suggest that tolerance to the hypnotic and hypothermic effects observed with these chlormethiazole treatment regimens was due to altered pharmacokinetics rather than to functional tolerance of the CNS.