Functional normalization of the hypothalamic-pituitary-adrenal axis in depressive patients by successful treatment with antidepressants is associated with increased efficiency of corticosteroid signal transduction. Accordingly, some antidepressants have been shown to influence the activity of the glucocorticoid receptor (GR) in cultured cells. It is not clear, however, whether this is a common principle for all antidepressants throughout all classes. Therefore, we screened a range of 18 antidepressants of different classes for their effect on GR signaling in a reporter gene assay using the mouse hippocampal cell line HT22. We evaluated GR-mediated gene transcription after short-time incubation (24 h) with different concentrations of each antidepressant (1 or 10 µM) in the presence or absence of the synthetic steroid dexamethasone (0.01 or 1 µM). The majority of antidepressants had a tendency to enhance steroid-induced GR-mediated gene transcription at high concentrations of antidepressant and low concentrations of steroid. Some antidepressants reduced the steroid-independent background activity of GR. This reduction was not due to unspecific inhibition of GR by oxidative stress, since no induction of intracellular peroxides was detectable in the concentration range of antidepressants used in our study. Furthermore, no significant change in GR activity was observed by concomitant treatment of HT22 cells with the antioxidant α-tocopherol (vitamin E). In conclusion, we report that many antidepressants enhance GR signaling in an in vitro neuronal system at clinically relevant concentrations. Those not showing an effect in vitro apparently use different mechanisms to influence GR activity that require an in vivo setting.
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