ABSTRACT
BACKGROUND: Astrocytes have been implicated in the pathophysiology of mood disorders and in the mechanism of the pharmacological effects of antidepressant drugs by the production of neurotrophic/growth factors. Previous studies have identified astrocyte-expressed Gαi/o -coupled lysophosphatidic acid receptor 1 (LPAR1), as being involved in antidepressant-induced production of glial cell line-derived neurotrophic factor (GDNF) and matrix metalloproteinase-9 (MMP-9) activation, an important step in the production of GNDF. However, the precise mechanism of MMP-9 activation by antidepressants has yet to be identified, in particular the intracellular signaling pathway between LPAR1/Gαi/o and MMP-9. METHODS AND RESULTS: Treatment of rat C6 astroglial cells (C6 cells) with amitriptyline increased Src family tyrosine kinase phosphorylation in a time and concentration-dependent manner. Amitriptyline-induced GDNF mRNA expression was blocked by Src family tyrosine kinase inhibitors. In addition, inhibiting Src family tyrosine kinase blocked amitriptyline-induced zymographic MMP-9 activation in C6 cells. The amitriptyline-induced zymographic MMP-9 activity was completely blocked by selective inhibition of Gαi/o protein and LPAR1. Furthermore, the amitriptyline-induced Src family tyrosine kinase phosphorylation was blocked by LPAR1, but not MMP-9 inhibition, indicating that Src family tyrosine kinase involvement is downstream of LPAR1. CONCLUSIONS: The current findings suggest that the pharmacological effect of antidepressant such as amitriptyline is mediated through an intracellular signaling pathway via the LPAR1/Gαi/o /Src family tyrosine kinase, which leads to MMP-9 activation and GDNF production.
