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 NH 2 -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.Major depression is a common and severe illness affecting a large number of individuals during their lifetime, and it is primarily treated with antidepressants. Most of the antidepressants are known to inhibit 5-hydroxytryptamine (serotonin, 5-HT) and/or noradrenaline (NA) reuptake; however, the efficacy of these antidepressants cannot be solely explained by their actions on the monoaminergic system. The molecular and cellular adaptations that underlie the therapeutic action of antidepressants have remained obscure. ; JNK, c-Jun NH 2 -terminal protein kinase; LDH, lactate dehydrogenase; ANOVA, analysis of variance; PLSD, protected least significant difference; HSD, honestly significant difference; MEK, mitogen-activated protein kinase kinase; PKA, protein kinase A; PKC, protein kinase C; DA, dopamine; PI3K, phosphoinositide-3 kinase; SP600125, anthra(1,9-cd)pyrazol-6(2H)-one.

Tricyclic Antidepressant Amitriptyline-induced Glial Cell Line-derived Neurotrophic Factor Production Involves Pertussis Toxin-sensitive Gαi/o Activation in Astroglial Cells

“…The tricyclic antidepressant amitriptyline increased GDNF production by astroglial cells through a monoamine-independent mechanism (9). The FGF receptor (FGFR)/FGFR substrate 2␣ (FRS2␣)/ERK signaling cascade plays a crucial role in amitriptyline-induced GDNF production, independent of monoamine activation (11).…”

Increased striatal serotonin synthesis following cortical resection in children with intractable epilepsy

“…Therefore, a better understanding of the role of striatal plasticity in reorganization of the brain following cortical injury or resection is essential to maximizing functional recovery. Serotonin is one of the major regulators of structural brain plasticity (Banasr et al, 2001;Brezun and Daszuta, 2000), not only functioning as a neurotransmitter, but also as a protective compound following brain injury (Kline et al, 2001), and an enhancer of axonal growth factors (Hisaoka et al, 2007). In order to study post-resection serotonergic alterations in human striatal circuitry, we evaluated postoperative images of serotonin synthesis in the thalamus and striatum using positron emission tomography (PET) and the tracer alpha[ 11 C]methyl-L-tryptophan (AMT) in children who had undergone epilepsy surgery.…”

The use of viral gene transfer in studies of brainstem noradrenergic and serotonergic neurons

“…According to the estimates made by Morin et al (1997), the density of b-adrenoreceptors is higher on astrocytes than on neurons isolated from the cortex and cerebellum. Interestingly, recent studies in a glioma C6 cell line suggest that 5HT may activate glial neurotrophic factor production (Hisaoka et al 2007;Tsuchioka et al 2008). Therefore, there is an intriguing possibility that at least some of the effects of NA or 5HT signalling in the brain involve astrocytes as intermediates (Stone & Ariano 1989).…”