Received for publication November 2, 2006.
Revised January 5, 2007.
Accepted for publication January 5, 2007.

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 MEK inhibitors. Indeed, treatment of amitriptyline rapidly increased ERK activity, as well as p38 MAPK and JNK 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 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 phospho-tyrosine 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.

Key words: ERK, GDNF, affective disorder, antidepressant, astrocytes, serotonin