title: Antidepressants increase glial cell line-derived neurotrophic factor production through monoamine-independent activation of protein tyrosine kinase and extracellular signal-regulated kinase in glial cells.
abstract: Recent studies show that neuronal and glial plasticity are important for therapeutic action of antidepressants. We previously reported that antidepressants increase glial cell line-derived neurotrophic factor (GDNF) production in rat C6 glioma cells (C6 cells). Here, we found that amitriptyline, a tricyclic antidepressant, increased both GDNF mRNA expression and release, which were selectively and completely inhibited by mitogen-activated protein kinase kinase inhibitors. Indeed, treatment of amitriptyline rapidly increased extracellular signal-regulated kinase (ERK) activity, as well as p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase activities. Furthermore, different classes of antidepressants also rapidly increased ERK activity. The extent of acute ERK activation and GDNF release were significantly correlated to each other in individual antidepressants, suggesting an important role of acute ERK activation in GDNF production. Furthermore, antidepressants increased the acute ERK activation and GDNF mRNA expression in normal human astrocytes as well as C6 cells. Although 5-hydroxytryptamine (serotonin) (5-HT), but not noradrenaline or dopamine, increased ERK activation and GDNF release via 5-HT2A receptors, ketanserin, a 5-HT2A receptor antagonist, did not have any effect on the amitriptyline-induced ERK activation. Thus, GDNF production by amitriptyline was independent of monoamine. Both of the amitriptyline-induced ERK activation and GDNF mRNA expression were blocked by genistein, a general protein tyrosine kinase (PTK) inhibitor. Actually, we found that amitriptyline acutely increased phosphorylation levels of several phosphotyrosine-containing proteins. Taken together, these findings indicate that ERK activation through PTK regulates antidepressant-induced GDNF production and that the GDNF production in glial cells may be a novel action of the antidepressant, which is independent of monoamine.
authors.affiliation: Institute of Clinical Research, Kure Medical Center, 3-1 Aoyama, Kure 737-0023, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Hisaoka
authors.forename: Minoru
authors.initials: M
authors.lastname: Takebayashi
authors.forename: Mami
authors.initials: M
authors.lastname: Tsuchioka
authors.forename: Natsuko
authors.initials: N
authors.lastname: Maeda
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakata
authors.forename: Shigeto
authors.initials: S
authors.lastname: Yamawaki
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology; D000928:Antidepressive Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009457:Neuroglia / Q000201:enzymology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D015306:Biogenic Monoamines; D051100:Glial Cell Line-Derived Neurotrophic Factor; D012333:RNA, Messenger; D000639:Amitriptyline; D012701:Serotonin; D007770:L-Lactate Dehydrogenase; D011505:Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases