The Antidepressant Amitriptyline Upregulates ERK1/2 Signaling and Inhibits Rho-Mediated Responses Induced by Lysophosphatidic Acid in Astroglial Cells

(1) Background. Different classes of antidepressant drugs have been shown to activate lysophosphatidic acid (LPA) receptors, but their effects on the receptor signaling stimulated by LPA have not fully investigated. In the present study, we examined the effect of the tricyclic antidepressant amitriptyline on LPA-induced activation of ERK1/2 and Rho signaling in C6 glioma cells and cultured rat astrocytes. (2) Methods. LPA receptor signaling was investigated by using Western blot and microscopic immunofluorescence assays. Rho activation was determined by a pull-down assay. (3) Results. Amitriptyline potentiated LPA-induced activation of ERK1/2 signaling, as indicated by the more than additive increases in the phosphorylation/activation of key components of this pathway, including fibroblast growth factor 1 receptor, MEK1/2, ERK1/2, Elk-1, and CREB. Amitriptyline also enhanced the expression of brain-derived neurotrophic factor (BDNF) elicited by LPA. In contrast, the antidepressant failed to mimic the LPA-induced activation of Rho and Rho-dependent responses, such as reversal of astrocyte stellation, accumulation of stress fibers, and phosphorylation of focal adhesion kinase and myosin target subunit of myosin phosphatase isoform 1. Moreover, when combined with LPA, amitriptyline curtailed Rho activation and the Rho-mediated cellular responses. (4) Conclusion. These results demostrate that in astroglial cells amitriptyline exerts a balanced action on LPA-activated receptors by enhancing the neuroprotective ERK1/2-CREB-BDNF signaling and dampening the potentially detrimental Rho-ROCK pathway, and suggest that this unique property may contribute to the antidepressant activity of the drug.