Effect of p-chlorophenylalanine on the acquisition of tolerance to the hypnotic effects of pentobarbital, barbital, and ethanol

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Abstract
Rats were given pentobarbital by daily intubation. Sleeping times and blood levels of drug at awakening, after i.p. test doses of ethanol, pentobarbital or barbital were measured at various times during chronic treatment to assess the degree of tolerance developed. No CNS tolerance to pentobarbital or cross-tolerance to barbital or ethanol occurred on treatment with sodium pentobarbital, 50 mg/kg daily. When the size and frequency of pentobarbital treatment doses were increased (50-80 mg/kg 3 times daily) a clear CNS tolerance to barbital occurred. Chronic administration of p-chlorophenylalanine (p-CPA), in a dose that maintains > 95% depletion of brain serotonin (5-HT) enhanced the acute hypnotic effect of barbiturates and ethanol. p-CPA treatment caused a reduction in the development of CNS tolerance. Brain 5-HT depletion may retard tolerance development to central depressant drugs as measured by a variety of unrelated tests.