Deconstructing Antiobesity Compound Action: Requirement of Serotonin 5-HT(2B) Receptors for Dexfenfluramine Anorectic Effects. - Archive ouverte HAL Access content directly
Journal Articles Neuropsychopharmacology Year : 2011

Deconstructing Antiobesity Compound Action: Requirement of Serotonin 5-HT(2B) Receptors for Dexfenfluramine Anorectic Effects.

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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-HT(2B) 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-HT(2B) 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-HT(2B) receptors (5-HT(2B)(-/-)). 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-HT(2B)(-/-) 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-HT(2B) receptors. These findings strongly suggest that activation of presynaptic 5-HT(2B) 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.
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Dates and versions

hal-00583533 , version 2 (21-12-2010)
hal-00583533 , version 1 (06-04-2011)

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Sophie M. Banas, Stéphane Doly, Katia Boutourlinsky, Silvina L. Diaz, Arnauld Belmer, et al.. Deconstructing Antiobesity Compound Action: Requirement of Serotonin 5-HT(2B) Receptors for Dexfenfluramine Anorectic Effects.: Anorectic compounds and 5-HTreceptors. Neuropsychopharmacology, 2011, 36 (2), pp.423-33. ⟨10.1038/npp.2010.173⟩. ⟨hal-00583533v2⟩
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