4.7 Article

Deconstructing Antiobesity Compound Action: Requirement of Serotonin 5-HT2B Receptors for Dexfenfluramine Anorectic Effects

Journal

NEUROPSYCHOPHARMACOLOGY
Volume 36, Issue 2, Pages 423-433

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/npp.2010.173

Keywords

behavior; feeding; receptor; releaser; serotonin; transporter

Funding

  1. Centre National de la Recherche Scientifique
  2. Institut National de la Sante et de la Recherche Medicale
  3. Universite Pierre et Marie Curie
  4. Fondation de France
  5. Fondation pour la Recherche Medicale
  6. Association pour la Recherche contre le Cancer
  7. French Ministry of Research (Agence Nationale pour la Recherche)
  8. European Union
  9. IBRO
  10. Region Ile de France DIM STEM
  11. Lefoulon-Delalande fellowship

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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. Neuropsychopharmacology (2011) 36, 423-433; doi:10.1038/npp.2010.173; published online 6 October 2010

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