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Inverse Agonist and Neutral Antagonist Actions of Antidepressants at Recombinant and Native 5-Hydroxytryptamine_2C Receptors: Differential Modulation of Cell Surface Expression and Signal Transduction

Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203, Universités de Montpellier, Montpellier, France (B.C., S.G., M.S., J.B., P.M.); Institut National de la Santé et de la Recherche Médicale U661, Montpellier, France (B.C., S.G., M.S., J.B., P.M.); Institut de Recherches Servier, Paris, France (B.C., C.M.L., M.J.M.); and Biocortech SAS, Paris, France (L.V., J.-F.P.)

Despite the importance of 5-hydroxytryptamine (5-HT)_2C (serotonin) receptors in the control of depressive states, actions of antidepressants at these receptors remain poorly characterized. This issue was addressed both in human embryonic kidney (HEK)-293 cells coexpressing unedited human 5-HT_2CINI receptors and G_q protein and in cultured mouse cortical neurons. Indicative of constitutive activity, the inverse agonist SB206,553 decreased basal inositol phosphate (IP) production in HEK-293 cells. The tetracyclic antidepressants mirtazapine and mianserin likewise suppressed basal IP formation. Conversely, the tricyclics amitriptyline and clomipramine, the m-chlorophenylpiperazine derivatives trazodone and nefazodone, and the 5-HT reuptake inhibitors fluoxetine and citalopram were inactive alone, although they blocked 5-HT-induced IP production. Inverse agonist actions of 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole (SB206,553) and mirtazapine were abolished by the neutral antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline (SB242,084), which was inactive alone. As assessed by confocal microscopy and enzyme-linked immunosorbent assay, prolonged treatment of HEK-293 cells with SB206,553, mirtazapine, or mianserin, but not the other antidepressants, enhanced cell surface expression of 5-HT_2C receptors: 5-HT-induced IP production was also increased, and both these actions were blocked by SB242,084. Cortical neurons were shown by reverse transcription-polymerase chain reaction to predominantly express constitutively active 5-HT_2C receptor isoforms. Prolonged pretreatment with SB206,553 or mirtazapine triggered an otherwise absent 5-HT-induced elevation in cytosolic Ca²⁺ concentrations. SB242,084, which was inactive alone, abolished these effects of SB206,553 and mirtazapine. In conclusion, the tetracyclic antidepressants mirtazapine and mianserin, but not other clinically established antidepressants, suppress constitutive activity at recombinant and native 5-HT_2C receptors. The clinical significance of inverse agonist versus neutral antagonist properties both during and after drug administration will be of interest to elucidate.

Address correspondence to: Dr. Joël Bockaert, Institut de Génomique Fonctionnelle, Universités de Montpellier, CNRS UMRS 5203, INSERM U661, 141 rue de la Cardonille, F-34094 Montpellier Cedex 5, France. E-mail: joel.bockaert{at}igf.cnrs.fr