title: Stimulation of catecholamine synthesis via activation of p44/42 MAPK in cultured bovine adrenal medullary cells by milnacipran.
abstract: Milnacipran is a serotonin noradrenaline reuptake inhibitor (SNRI) and is used clinically as an antidepressant. We report here the effect of milnacipran on catecholamine synthesis in cultured bovine adrenal medullary cells. Incubation of adrenal medullary cells with milnacipran (300 ng/ml, 1,065 nM) for 20 min resulted in a significant increase in 14C-catecholamine synthesis from [14C]tyrosine, but not from [14C]DOPA, whereas the selective serotonin reuptake inhibitors (SSRIs), paroxetine (300 ng/ml, 800 nM) and fluvoxamine (300 ng/ml, 691 nM), had little effect. Milnacipran, but not paroxetine or fluvoxamine, increased the activity of tyrosine hydroxylase, the rate-limiting step of catecholamine biosynthesis, in a concentration-dependent manner (100-300 ng/ml, 355-1,065 nM). U0126 (1 microM), an inhibitor of p44/42 mitogen-activated protein kinase (MAPK) kinase, abolished the stimulatory effects of milnacipran on tyrosine hydroxylase activity. Furthermore, incubation of cells with milnacipran (30-100 ng/ml) for 5 min activated p44/42 MAPK, whereas paroxetine and fluvoxamine did not. The present findings suggest that milnacipran activates tyrosine hydroxylase and then stimulates catecholamine synthesis through a p44/42 MAPK-dependent pathway in cultured bovine adrenal medullary cells.
authors.affiliation: Department of Psychiatry, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, 807-8555, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Shinkai
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Toyohira
authors.forename: Reiji
authors.initials: R
authors.lastname: Yoshimura
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
authors.forename: Susume
authors.initials: S
authors.lastname: Ueno
authors.forename: Jun
authors.initials: J
authors.lastname: Nakamura
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
mesh_terms: D000313:Adrenal Medulla / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002395:Catecholamines / Q000096:biosynthesis*; D002417:Cattle; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000494:pharmacology*; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D016666:Fluvoxamine / Q000494:pharmacology; D000078764:Milnacipran; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D002070:Butadienes; D002395:Catecholamines; D003521:Cyclopropanes; D004295:Dihydroxyphenylalanine; D016666:Fluvoxamine; D000078764:Milnacipran; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009570:Nitriles; D017374:Paroxetine; D047428:Protein Kinase Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors; D014443:Tyrosine; D014446:Tyrosine 3-Monooxygenase; C113580:U 0126