Antidepressant drugs inhibit glucocorticoid receptor-mediated gene transcription - a possible mechanism

1 Antidepressant drugs are known to inhibit some changes evoked by glucocorticoids, as well as a hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis, often observed in depression. 2 The aim of present study was to investigate effects of various antidepressant drugs on the glucocorticoid-mediated gene transcription in fibroblast cells, stably transfected with an MMTV promoter (LMCAT cells). 3 The present study have shown that antidepressants (imipramine, amitriptyline, desipramine, fluoxetine, tianeptine, mianserin and moclobemide), but not cocaine, inhibit the corticosterone-induced gene transcription in a concentration- and a time-dependent manner. 4 Drugs which are known to augment clinical effects of medication in depressed patients (lithium chloride, amantadine, memantine), do not affect the inhibitory effects of imipramine on the glucocorticoid receptor (GR)-mediated gene transcription. 5 Inhibitors of phospholipase C (PLC), protein kinase C (PKC), Ca2+/calmodulin-dependent protein kinase (CaMK) and antagonists of the L-type Ca2+ channel also inhibit the corticosterone-induced gene transcription. 6 Inhibitors of protein kinase A (PKA) and protein kinase G (PKG) are without effect on the GR-induced gene transcription. 7 Phorbol ester tan activator of PI(C) attenuates the inhibitory effect of imipramine on the GR-induced gene transcription. 8 Imipramine decreases binding of corticosterone-receptor complex to DNA. 9 It is concluded that antidepressant drugs inhibit the corticosterone-induced gene transcription, and that the inhibitory effect of imipramine depends partly on the PLC/PKC pathway.