Functional tolerance to chlormethiazole and cross-tolerance to ethanol in the rat: importance of test and mode of drug administration.

Tolerance to the effects of chlormethiazole on circular maze performance, and cross-tolerance to ethanol, were investigated in rats. Tolerance to chlormethiazole in the moving belt test was also measured in the same rats. Treatment with a total daily dose of subcutaneous chlormethiazole, 200 mg/kg, for 20 days produced clear tolerance to chlormethiazole and cross-tolerance to ethanol in the circular maze test. This treatment, however, failed to produce tolerance to chlormethiazole in the moving belt test. No evidence of physical dependence was found. In other studies, continuous intravenous infusion of chlormethiazole, 30-50 mg/kg/h for 9 days, resulted in clear functional tolerance to chlormethiazole and cross-tolerance to ethanol in the moving belt test. Similarly, chronic ethanol treatment, 4-6 g/kg daily for 3 weeks, resulted in functional tolerance to ethanol and cross-tolerance to chlormethiazole in the same test. These results indicate that the demonstration of functional tolerance to chlormethiazole and cross-tolerance to ethanol is dependent both on the sensitivity of the behavioural measurement tests employed, and on the degree of continuity of exposure of the central nervous system to the drug. It is concluded that, for doses that are equipotent in acute log-dose studies, chlormethiazole produces less tolerance and physical dependence than ethanol, perhaps because of a shorter half-life.