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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]