title: Inverse agonist and neutral antagonist actions of antidepressants at recombinant and native 5-hydroxytryptamine2C receptors: differential modulation of cell surface expression and signal transduction.
abstract: 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 Galpha(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 Ca(2+) 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.
authors: Institut de Génomique Fonctionnelle, Universités de Montpellier, CNRS UMRS 5203, INSERM U661, 141 rue de la Cardonille, F-34094 Montpellier Cedex 5, France.
authors: Benjamin
authors: B
authors: Chanrion
authors: Clotilde
authors: C
authors: Mannoury la Cour
authors: Sophie
authors: S
authors: Gavarini
authors: Mathieu
authors: M
authors: Seimandi
authors: Laurent
authors: L
authors: Vincent
authors: Jean-François
authors: JF
authors: Pujol
authors: Joël
authors: J
authors: Bockaert
authors: Philippe
authors: P
authors: Marin
authors: Mark J
authors: MJ
authors: Millan
mesh_terms: D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D007295:Inositol Phosphates / Q000032:analysis / Q000096:biosynthesis; D007668:Kidney / Q000166:cytology; D009474:Neurons / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D000929:Antidepressive Agents, Tricyclic; D007295:Inositol Phosphates; D012333:RNA, Messenger; D044405:Receptor, Serotonin, 5-HT2C; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D043802:GTP-Binding Protein alpha Subunits, Gq-G11