QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.116558v1 321/1/148    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hisaoka, K. Articles by Yamawaki, S. Search for Related Content PubMed PubMed Citation Articles by Hisaoka, K. Articles by Yamawaki, S.

NEUROPHARMACOLOGY

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

Institute of Clinical Research (K.H., Mi.T., Ma.T., N.M.) and Department of Psychiatry (Mi.T.), National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, Kure, Japan; and Department of Pharmacology, Division of Clinical Pharmaceutical Sciences, Programs of Pharmaceutical Sciences (Ma.T., Y.N.) and Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research (S.Y.), Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan

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-HT_2A receptors, ketanserin, a 5-HT_2A 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.

Address correspondence to: Dr. Minoru Takebayashi, Department of Psychiatry and Institute of Clinical Research, National Kure Medical Center, 3-1 Aoyama, Kure 737-0023, Japan. E-mail: mtakebayashi{at}kure-nh.go.jp