Received for publication October 9, 2007.
Revised November 19, 2007.
Accepted for publication November 20, 2007.

Chronic Fenfluramine Administration Increases Plasma Serotonin (5-HT) to Non-Toxic Levels

Abstract

Large elevations in blood serotonin (5-HT) can produce valvular heart disease in humans and laboratory animals. Accordingly, one prevailing hypothesis (i.e., the "5-HT hypothesis") suggests 5-HT transporter substrates like fenfluramine increase the risk for valvular heart disease by elevating plasma 5-HT, secondary to the release of 5-HT from platelets. The main purpose of this study was to determine if chronic administration of fenfluramine increases plasma 5-HT to concentrations that are associated with the development of valvular heart disease. To the best of our knowledge, this is the first study to address this issue using an in vivo microdialysis method that measures plasma 5-HT in non-hypoxic rats. We examined the effects of chronic (±)-fenfluramine and fluoxetine on plasma levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in blood samples from conscious catheterized rats. Plasma indoles were measured by HPLC-ECD in dialysates of whole blood. Baseline plasma 5-HT was < 1.0 nM. Chronic fenfluramine (14-day minipump infusion) produced small increases in baseline plasma 5-HT (~2-to-4-fold), while chronic fluoxetine had no effect. Chronic fenfluramine and fluoxetine markedly decreased whole blood 5-HT, and reduced the ability of acute fenfluramine to evoke 5-HT release. Elevations in baseline plasma 5-HT produced by chronic fenfluramine are far below µM levels necessary to produce valvular heart disease. Furthermore, chronic fenfluramine reduces the ability of acute fenfluramine to increase plasma 5-HT, suggesting the "5-HT hypothesis" can not explain the increased risk of valvular heart disease in patients treated with fenfluramine.

Key words: fenfluramine, fluoxetine, plasma serotonin, platelet, pulmonary hypertension, valvular heart disease