Differential effects of antidepressants on dexamethasone-induced nuclear translocation and expression of glucocorticoid receptor

The glucocorticoid receptor (GR) is a key regulator of the hypothalamic–pituitary–adrenal (HPA) axis. Mood disorder patients often exhibit abnormalities in this axis. Although the clinical benefit of antidepressants is associated with the normalization of the disturbed HPA activity by enhanced negative feedback of the HPA axis, the precise mechanism remains unknown. In order to examine the effect of antidepressants on the translocation of GR into the nucleus, we performed time-lapse observation on SY5Y cells that had been transiently transfected with plasmids expressing the green fluorescence protein (GFP)-tagged GRα. Clomipramine and desipramine facilitated dexamethasone (Dex)-induced GFP-GRα nuclear translocation. Coincubation of verapamil, an inhibitor of membrane steroid transporters, showed little or no additive effect on GFP-GRα nuclear translocation induced by both Dex and clomipramine. In the absence of Dex, antidepressants did not induce the translocation of GFP-GRα into the nucleus. Using real-time PCR, we examined the effect of antidepressants on splicing isoform of GR, GRα, and GRβ in SY5Y and Jurkat cells. Incubation with paroxetine and desipramine for 48 h and 7 days increased GRα expression, whereas the expression of GRβ remained stable. Antidepressants did not alter the expression of SRp30c that is associated with alternative splicing of GR transcript. Thus, antidepressants exert differential effects on the translocation and expression of GR to enhance GR signaling.