Deconstructing antiobesity compound action : requirement of serotonin 5-HT2B receptors for dexfenfluramine anorectic effects
Banas, Sophie M., Doly, Stephane, Boutourlinsky, Katia, Diaz, Silvina L., Belmer, Arnauld, Callebert, Jacques, Collet, Corinne, Launay, Jean-Marie, & Maroteaux, Luc (2011) Deconstructing antiobesity compound action : requirement of serotonin 5-HT2B receptors for dexfenfluramine anorectic effects. Neuropsychopharmacology, 36(2), pp. 423-433.
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 dependent-releasing effect of dexfenfluramine, whereas other serotonin receptors act downstream with respect to feeding behavior.
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|Item Type:||Journal Article|
|Keywords:||amphetamine derivatives, 5-HT2B, anorectic compounds|
|Subjects:||Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > NEUROSCIENCES (110900) > Neurosciences not elsewhere classified (110999)|
|Divisions:||Current > Schools > School of Clinical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
|Deposited On:||19 Aug 2014 22:37|
|Last Modified:||21 Aug 2014 01:07|
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