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Coincidence of blockade of synaptosomal 5-hydroxytryptamine uptake and decrease in tryptophan hydroxylase activity: effects of fenfluramine.

A single injection of fenfluramine hydrochloride resulted in a short-term increase in striate synaptosomal conversion of tryptophan to serotonin (5-HT) in rat brain. In contrast, D- and L-amphetamine sulfate resulted in a short-term decrease of this index of 5-HT biosynthesis. None of the amphetamines studied altered the kinetics of synaptosomal uptake of L-[3-14C]-tryptophan measured in the same striate preparation. Within 4 hours after fenfluramine administration, 3H-5-HT uptake into synaptosomes was markedly decreased; it returned to control levels in 10 to 14 days. Intrasynaptosomal tryptophan hydroxylase activity dropped markedly within 4 hours of drug administration and remained depressed for 10 to 14 days, its return to control levels coinciding with that of 3H-5-HT uptake. Only 5-HT cell body enzyme prepared from the lateral midbrain (B9) demonstrated a reduction in activity comparable to that seen in the synaptosomes; very small decreases occurred in cell body enzyme prepared from whole midbrain (B7, B8, B9) or medial midbrain (B7, B8). Lateral midbrain tryptophan hydroxylase activity returned to control levels by 8 days. In vitro, fenfluramine (100 muM) affected none of these indices of central 5-HT synthesis except 3H-5-HT uptake, which it reduced, and synaptosomal 3H-5-HT release, which it facilitated. The effects of fenfluramine on 5-HT biosynthesis persisted longer than those of D-amphetamine, which lasted less than 24 hours. However, the fenfluramine effects were much shorter than those reported for p-chloroamphetamine, which persist for up to 3 months. These three amphetamines apparently affect the lateral midbrain raphe nuclei selectively.