SPECIES-DIFFERENCES IN THE RATE OF DISAPPEARANCE OF FENFLURAMINE AND ITS EFFECTS ON BRAIN-SEROTONIN NEURONS

A single injection of fenfluramine, the m-trifluoromethyl-N-ethyl derivative of amphetamine, produces long-term decreases in brain levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan hydroxylase activity (TPH), and the synaptosomal uptake of [3H]-5-HT in rats. In order to test the extent to which similar effects occur in mice, rats and mice were injected with various doses of fenfluramine and killed 2 weeks later for the determination of 5-HT and 5-HIAA in one half of the brain, 5-HT uptake in the hippocampus from the other half, and TPH in the remaining tissue. A dose of 20 mg/kg produced marked reductions in 5-HT and 5-HIAA in rats, while in mice significant reductions in both of these parameters were observed only after 80 mg/kg. TPH was diminished after 60 mg/kg in rats but not after any dose up to 80 mg/kg in mice. A 58 percent reduction in 5-HT uptake occurred after 40 mg/kg in rats and 80 mg/kg in mice. Complete recovery was evident by 2 months after the administration of fenfluramine to mice when, as indicated by previous reports, marked effects are still present in rats. These results demonstrate that mice are substantially less sensitive than rats to the long-term effects of fenfluramine on central 5-HT systems. In addition, the half-lives of fenfluramine and its active metabolite, norfenfluramine. were much shorter in mice than in rats. Thus, the rates of disappearance of fenfluramine and norfenfluramine are correlated with, and perhaps determine, the extent to which the administration of fenfluramine produces longterm, neurotoxic effects on central 5-HT mechanisms in rats and mice. © 1979.