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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 Gα i/o ‐coupled lysophosphatidic acid receptor 1 ( LPAR 1), 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  LPAR 1/Gα i/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 Gα i/o  protein and  LPAR 1. Furthermore, the amitriptyline‐induced Src family tyrosine kinase phosphorylation was blocked by  LPAR 1, but not  MMP ‐9 inhibition, indicating that Src family tyrosine kinase involvement is downstream of  LPAR 1.    Conclusions  The current findings suggest that the pharmacological effect of antidepressant such as amitriptyline is mediated through an intracellular signaling pathway via the  LPAR 1/Gα i/o /Src family tyrosine kinase, which leads to  MMP ‐9 activation and  GDNF  production.

neuropsychopharmacology reports

Antidepressant amitriptyline‐induced matrix metalloproteinase‐9 activation is mediated by Src family tyrosine kinase, which leads to glial cell line‐derived neurotrophic factor  mRNA  expression in rat astroglial cells