Serotonin Transporters, Serotonin Release, and the Mechanism of Fenfluramine Neurotoxicity
| Autor: | Mario A. Ayestas, John S. Partilla, Richard B. Rothman, Christina M. Dersch, Michael H. Baumann |
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| Rok vydání: | 2000 |
| Předmět: |
Male
Agonist Serotonin medicine.medical_specialty Microdialysis Fenfluramine medicine.drug_class Dopamine Models Neurological Pharmacology Nucleus accumbens Biology Tritium Piperazines General Biochemistry Genetics and Molecular Biology Rats Sprague-Dawley Dopamine Uptake Inhibitors History and Philosophy of Science Internal medicine Electrochemistry medicine Animals Chromatography High Pressure Liquid Brain Chemistry Analysis of Variance Dose-Response Relationship Drug General Neuroscience Neurotoxicity Brain medicine.disease Rats Serotonin Receptor Agonists Disease Models Animal Endocrinology Forebrain Neurotoxicity Syndromes Selective Serotonin Reuptake Inhibitors medicine.drug |
| Zdroj: | Annals of the New York Academy of Sciences. 914:172-186 |
| ISSN: | 0077-8923 |
| Popis: | Administration of d,l-fenfluramine (FEN), or the more active isomer d-fenfluramine (dFEN), causes long-term depletion of forebrain serotonin (5-HT) in animals. The mechanism underlying FEN-induced 5-HT depletion is not known, but appears to involve 5-HT transporters (SERTs) in the brain. Some investigators have postulated that 5-HT release evoked by FEN is responsible for the deleterious effects of the drug. In the present work, we sought to examine the relationship between drug-induced 5-HT release and long-term 5-HT depletion. The acute 5-HT-releasing effects of dFEN and the non-amphetamine 5-HT agonist 1-(m-chlorophenyl)piperazine (mCPP) were evaluated using in vivo microdialysis in rat nucleus accumbens. The ability of dFEN and mCPP to interact with SERTs was assessed using in vitro assays for [3H]-transmitter uptake and release in rat forebrain synaptosomes. Drugs were subsequently tested for potential long-lasting effects on brain tissue 5-HT after repeated dosing (2.7 or 8.1 mg/kg, ip × 4). dFEN and mCPP were essentially equipotent in their ability to stimulate acute 5-HT release in vivo and in vitro. Both drugs produced very selective effects on 5-HT with minimal effects on dopamine. Interestingly, when dFEN or mCPP was administered repeatedly, only dFEN caused long-term 5-HT depletion in the forebrain at 2 weeks later. These data suggest that acute 5-HT release per se does not mediate the long-term 5-HT depletion associated with dFEN. We hypothesize that dFEN and other amphetamine-type releasers gain entrance into 5-HT neurons via interaction with SERTs. Once internalized in nerve terminals, drugs accumulate to high concentrations, causing damage to cells. The relevance of this hypothesis for explaining clinical side effects of FEN and dFEN, such as cardiac valvulopathy and primary pulmonary hypertension, warrants further study. |
| Databáze: | OpenAIRE |
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