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

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

Modulation of serotonergic function in rat brain by VN2222, a 5-HT reuptake inhibitor with 5-HT1A receptor agonist

VN2222 (1-(benzo[b]thiophen-3-yl)-3-[4-(2-methoxiphenyl piperazin-1-yl]propan-1-ol) is a potential antidepressant with high affinity for the serotonin transporter and 5-HT1A receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HText) in rat striatum to 780% of baseline whereas its systemic administration (1–10 mg/kg s.c.) reduced 5-HText. In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HText. Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED50: 790, 14.9, and 0.8 g/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT1A receptors as assessed by microdialysis and single-unit recordings (ED50 values for 8-OH-DPAT were 0.45 and 2.34 g/kg i.v. for controls and rats treated with 6 mg/kg day VN2222). These results show that VN2222 is a mixed 5-HT reuptake inhibitor/5-HT1A agonist that markedly desensitizes 5-HT1A autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug.Peer reviewe

Dating the geologic history of Oman's Semail ophiolite: insights from U-Pb geochronology

Eclogites from the deepest structural levels beneath the Semail ophiolite, Oman, record the subduction and later exhumation of the Arabian continental margin. Published ages for this high pressure event reveal large discrepancies between the crystallisation ages of certain eclogite-facies minerals and apparent cooling ages of micas. We present precise U-Pb zircon (78.95 ± 0.13 Ma) and rutile (79.6 ± 1.1 Ma) ages for the eclogites, as well as new U-Pb zircon ages for trondhjemites from the Semail ophiolite (95.3 ± 0.2 Ma) and amphibolites from the metamorphic sole (94.48 ± 0.23 Ma). The new eclogite ages reinforce published U-Pb zircon and Rb-Sr mineral-whole rock isochron ages, yet are inconsistent with published interpretations of older 40Ar/39Ar phengite and Sm-Nd garnet dates. We show that the available U-Pb and Rb-Sr ages, which are in tight agreement, fit better with the available geological evidence, and suggest that peak metamorphism of the continental margin occurred during the later stages of ophiolite emplacement