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The effects of 5,7-dihydroxytryptamine and L-tryptophan treatment on ethanol tolerance in the rat, as measured by the moving-belt test of motor impairment and by hypothermia, were examined in separate studies. A 2 × 2 design was used for all experiments. 5,7-Dihydroxy-tryptamine (200 μg in 20 μl CSF) or vehicle alone was administered once into both lateral ventricles of the rat. Desmethylimipramine was administered intraperitoneally prior to an intraventricular injection of 5,7-dihydroxytryptamine to prevent the destruction of norepinephrine. L-Tryptophan (75 mg/kg p.o. twice daily) or water was administered chronically. Ethanol (4-5 g/kg p.o.) or sucrose was given daily, and the development of tolerance was monitored at5-7-day intervals. Chronic ethanol treatment produced tolerance to both the motor impairment and hypothermia effects of ethanol. 5,7-Dihydroxytryptamine and L-tryptophan treatment did not alter either the motor impairment or hypothermia produced by the initial dose of ethanol. 5,7-Dihydroxytryptamine produced a 75% depletion of brain 5-HT and slowed the development of tolerance to ethanol in both measurements. In contrast, elevation of 5-HT by L-tryptophan (39% increase by a single dose) facilitated the development of tolerance to ethanol, as seen in both measures. These findings support our hypothesis that brain 5-HT has a modulating role in the development of tolerance to ethanol. [ABSTRACT FROM AUTHOR]

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.