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- Title
Deconstructing Antiobesity Compound Action: Requirement of Serotonin 5-HT<sub>2B</sub> Receptors for Dexfenfluramine Anorectic Effects.
- Authors
Banas, Sophie M.; Doly, Stéphane; Boutourlinsky, Katia; Diaz, Silvina L; Belmer, Arnauld; Callebert, Jacques; Collet, Corinne; Launay, Jean-Marie; Maroteaux, Luc
- Abstract
The now-banned anorectic molecule, dexfenfluramine, promotes serotonin release through a serotonin transporter-dependent mechanism, and it has been widely prescribed for the treatment of obesity. Previous studies have identified that 5-HT2B receptors have important roles in dexfenfluramine side effects, that is, pulmonary hypertension, plasma serotonin level regulation, and valvulopathy. We thus investigated a putative contribution of 5-HT2B receptors in dexfenfluramine-dependent feeding behavior in mice. Interestingly, the hypophagic response to dexfenfluramine (3-10 mg/kg) observed in wild-type mice (1-4 h) was eliminated in mice lacking 5-HT2B receptors (5-HT2B−/−). These findings were further validated by the lack of hypophagic response to dexfenfluramine in wild-type mice treated with RS127445, a highly selective and potent antagonist (pKi=8.22±0.24). Using microdialysis, we observed that in 5-HT2B−/− awake mice, the dexfenfluramine-induced hypothalamic peak of serotonin release (1 h) was strongly reduced (fourfold) compared with wild type. Moreover, using hypothalamic synaptosomes, we established the serotonergic neuron autonomous properties of this effect: a strong serotonin release was observed upon dexfenfluramine stimulation of synaptosome preparation from wild type but not from mice lacking active 5-HT2B receptors. These findings strongly suggest that activation of presynaptic 5-HT2B receptors is a limiting step in the serotonin transporter dependant-releasing effect of dexfenfluramine, whereas other serotonin receptors act downstream with respect to feeding behavior.
- Subjects
OBESITY; APPETITE depressants; DEXFENFLURAMINE; SEROTONIN; MICE
- Publication
Neuropsychopharmacology, 2011, Vol 36, Issue 2, p423
- ISSN
0893-133X
- Publication type
Article
- DOI
10.1038/npp.2010.173