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

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2011-01, Vol.36 (2), p.423-433
• Main Authors: Banas, Sophie M, Doly, Stephane, Boutourlinsky, Katia, Diaz, Silvina L, Belmer, Arnauld, Callebert, Jacques, Collet, Corinne, Launay, Jean-Marie, Maroteaux, Luc
• Format: Article
• Language: English
• ISSN: 0893-133X
• DOI: 10.1038/npp.2010.173

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 sub(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 sub(2B) receptors in dexfenfluramine-dependent feeding behavior in mice. Interestingly, the hypophagic response to dexfenfluramine (3-10mg/kg) observed in wild-type mice (1-4h) was eliminated in mice lacking 5-HT sub(2B) receptors (5-HT sub(2B) super(-/-)). 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 plus or minus 0.24). Using microdialysis, we observed that in 5-HT sub(2B) super(-/-) awake mice, the dexfenfluramine-induced hypothalamic peak of serotonin release (1h) 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 sub(2B) receptors. These findings strongly suggest that activation of presynaptic 5-HT sub(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.