期刊
NEUROPSYCHOPHARMACOLOGY
卷 36, 期 2, 页码 423-433出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/npp.2010.173
关键词
behavior; feeding; receptor; releaser; serotonin; transporter
资金
- Centre National de la Recherche Scientifique
- Institut National de la Sante et de la Recherche Medicale
- Universite Pierre et Marie Curie
- Fondation de France
- Fondation pour la Recherche Medicale
- Association pour la Recherche contre le Cancer
- French Ministry of Research (Agence Nationale pour la Recherche)
- European Union
- IBRO
- Region Ile de France DIM STEM
- Lefoulon-Delalande fellowship
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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