p-CHLOROAMPHETAMINE: IN VIVO INVESTIGATIONS ON THE MECHANISM OF ACTION OF THE SELECTIVE DEPLETION OF CEREBRAL SEROTONIN

¹ Psychopharmacology Research Center, Department of Pharmacology, Vanderbilt, University School of Medicine, Nashville, Tennessee

The present investigations were undertaken to study the mechanism by which p-chloramphetamine decreases both serotonin (5-HT) and 5-hydroxyindole acetic acid in the brains of rats. 1) Doses of p-chloroamphetamine, which markedly reduced the level of endogenous 5-HT in brain, failed to decrease labeled 5-HT derived from either intraventricularly administered 5-HT-H³ or 5-hydroxytryptophan-C¹⁴. Under similar conditions, reserpine and RO 4-1284 caused a striking reduction of both the endogenous and the labeled 5-HT. 2) p-Chloroamphetamine partially blocked the increase of endogenous brain 5-HT but not that of brain norepinephrine, after monoamine oxidase inhibition by pargyline. 3) The increase in brain 5-hydroxyindole acetic acid resulting from the administration of probenecid was almost completely blocked in animals treated 48 and 24 hours previously with p-chloroamphetamine. This blockade was not evident when p-chloroamphetamine was administered 10 minutes prior to probenecid. 4) Like p-chlorophenylaline, p-chloroamphetamine caused a decrease in the amount of 5-HT-C¹⁴ in brain formed from intraventricularly administered tryptophan-C¹⁴; however, it did not change the amount of 5-HT-C¹⁴ derived from intraventricular 5-hydroxytryptophan-C¹⁴ 5) p-Chloroamphetamine did not alter the level of either endogenous tryptophan or tryptophan-C¹⁴ taken up into the brain from the ventricular system. On the basis of these experimental data, it is concluded that p-chloroamphetamine impairs the synthesis of cerebral 5-HT. Moreover, the results of these studies in vivo implicate an inhibition of cerebral tryptophan hydroxylase in the simultaneous lowering of cerebral 5-HT and 5-hydroxyindole acetic acid by p-chloroamphetamine.

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