Chronic Fenfluramine Administration Increases Plasma Serotonin (5-Hydroxytryptamine) to Nontoxic Levels
- Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland
- Address correspondence to:
Dr. Richard B. Rothman, Clinical Psychopharmacology, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Heath and Human Services, 5500 Nathan Shock Dr., Baltimore, MD 21224. E-mail: rrothman{at}intra.nida.nih.gov
Abstract
Large elevations in blood serotonin (5-hydroxytryptamine; 5-HT) can produce valvular heart disease in humans and laboratory animals. In accordance, one prevailing hypothesis (i.e., the “5-HT hypothesis”) suggests that 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 whether 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 nonhypoxic 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 high-performance liquid chromatography with electrochemical detection in the dialysates of whole blood. The baseline plasma 5-HT level was <1.0 nM. Chronic fenfluramine (14-day minipump infusion) produced small increases in baseline plasma 5-HT (∼2–4-fold), whereas 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 the micromolar levels necessary to produce valvular heart disease. Furthermore, chronic fenfluramine reduces the ability of acute fenfluramine to increase plasma 5-HT, suggesting that the 5-HT hypothesis cannot explain the increased risk of valvular heart disease in patients treated with fenfluramine.
Footnotes
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This research was generously supported by the Intramural Research Program of the National Institute on Drugs Abuse, National Institutes of Health, Department of Heath and Human Services.
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The data presented here have appeared in abstract form as follows: Zolkowska D, Baumann MH, and Rothman RB (2006) Effects of acute and chronic fenfluramine on plasma concentrations of serotonin in rats. Evolution of Pulmonary Hypertension: Emerging Diseases and Novel Therapeutics Meeting; 2006 Dec 7–8; NHLBI, National Institutes of Health, Bethesda, MD; Zolkowska D, Baumann MH, and Rothman RB (2006) Effect of chronic administration of fenfluramine and fluoxetine on fenfluramine-induced increases in plasma serotonin in rats. 2006 American College of Neuropsychopharmacology 45th Annual Meeting; 2006 Dec 5; Hollywood, FL. American College of Neuropsychopharmacology, Nashville, TN; and Zolkowska D, Baumann MH, and Rothman RB (2006) Effects of acute and chronic administration of psychostimulants on plasma concentrations of serotonin in rats. Society for Neuroscience, 36th Annual Meeting; 2006 Oct 16; Atlanta, GA. Society for Neuroscience, Washington DC.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.132654.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine; SERT, serotonin transporter protein; 5-HIAA, 5-hydroxyindoleacetic acid; VHD, valvular heart disease; IPAH, idiopathic primary pulmonary hypertension; HPLC-ECD, high-performance liquid chromatography with electrochemical detection; RIA, radioimmunoassay.
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- Received October 4, 2007.
- Accepted November 20, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
