Effect of p-chloroamphetamine on cerebral tryptophan-5-hydroxylase in vivo: A reexamination

Abstract

p-Chloroamphetamine ( p-CA) (10 mg/kg i.p.) exerts two distinct effects: a short-term one lasting 48 hr and long-term one responsible for the progressive decrease in levels of serotonin (5-HT) and in hydroxylation of tryptophan. In two weeks there was a 40 per cent concurrent reduction in the hydroxylation of tryptophan, in the V max of tryptophan hydroxylase from brainstem, in the recovery of the total enzyme units, and in the turnover rate of 5-HT. None of these effects were observed after intraventricular injection of 200 μg of p-CA. The uptake of [ 3H]-5-HT by synaptosomal fractions from various areas of the brain at 3 and 14 days after p-CA treatment revealed marked impairment in the high affinity uptake. This did not occur 3 days after administration of p-chlorophenylalanine. These changes are interpreted as the outcome of neurotoxicity brought about by a metabolite of p-CA which would specifically affect the serotoninergic system. A hypothetical scheme for the biological synthesis of such a metabolite is given. The concept of irreversible inactivation of tryptophan hydroxylase by p-CA is inconsistent with experimental evidence.