Antidepressant drugs inhibit glucocorticoid receptor‐mediated gene transcription – a possible mechanism

Abstract

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. 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). 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. 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. 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. Inhibitors of protein kinase A (PKA) and protein kinase G (PKG) are without effect on the GR‐induced gene transcription. Phorbol ester (an activator of PKC) attenuates the inhibitory effect of imipramine on the GR‐induced gene transcription. Imipramine decreases binding of corticosterone‐receptor complex to DNA. 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. British Journal of Pharmacology (2000) 130, 1385–1393; doi:

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

“…These findings are remarkably consistent with previous work in cell lines, by us and others, showing that antidepressants are unable to potentiate GR-mediated gene transcription in the presence of an MDR PGP inhibitor or of a glucocorticoid that is not transported by MDR PGP (Pariante et al, 1997(Pariante et al, , 2001(Pariante et al, , 2003a(Pariante et al, , b, 2004bBudziszewska et al, 2000;Miller et al, 2002;Herr et al, 2003). Moreover, we find that desipramine reduces MDR PGP (Mdr1a) expression in the hippocampus of FVB/N control controls, again consistent with previous work in cell lines (Varga et al, 1996;Szabo et al, 1999;Weiss et al, 2003;Pariante et al, 2003b;Weber et al, 2005).…”

“…Indeed, we have recently described that the tricyclic antidepressant, clomipramine, increases the intracellular concentration of glucocorticoids in rat cortical neurons, where MDR PGP has not been described (Pariante et al, 2003a). Alternatively, or additionally, antidepressants can activate the GR by regulating a variety of secondmessenger mechanisms (Maes et al, 1999;Budziszewska et al, 2000;Basta-Kaim et al, 2002, 2004, 2006Budziszewska et al, 2004;Yehuda et al, 2004Yehuda et al, , 2006Wang et al, 2005). Incidentally, we show here that one important pathway regulating glucocorticoid action in the brain, the enzyme 11b-HSD1 (Seckl and Walker, 2001), is not regulated by desipramine.…”

“…Consistent with this finding, pretreatment of cells with an MDR PGP inhibitor, or coincubation with a glucocorticoid that is not transported by MDR PGP in vitro, prevents these effects of antidepressants (Pariante et al, 1997(Pariante et al, , 2001(Pariante et al, , 2003a. Although other researchers have independently replicated these in vitro findings (Budziszewska et al, 2000;Miller et al, 2002;Herr et al, 2003), this model has never been directly tested in animals.…”

The Antidepressant Clomipramine Regulates Cortisol Intracellular Concentrations and Glucocorticoid Receptor Expression in Fibroblasts and Rat Primary Neurones

“…We have used clomipramine, at 10 mM, for 24 h, as previously described (Pariante et al, 2001a). In vitro treatment with micromolar concentrations of antidepressants for at least 24 h have been previously used in studies that have investigated the in vitro effects of antidepressants on the GR (Pariante et al, 1997(Pariante et al, , 2001aVedder et al, 1999;Budziszewska et al, 2000;Miller et al, 2002;Lai et al, 2003) or on other molecular systems (Chen and Rasenick, 1995;Varga et al, 1996;Szabo et al, 1999;Xia et al, 1999;Maes et al, 1999). Moreover, this concentration resembles the therapeutic plasma and brain levels of tricyclic antidepressants (Hrdina and Dubas, 1981;Glotzbach and Preskorn, 1982).…”

“…Antidepressants increase GR function and GR expression in neuronal cell cultures (Pepin et al, 1989;Okugawa et al, 1999;Hery et al, 2000;Lai et al, 2003), fibroblasts (Pepin et al, 1992;Pariante et al, 1997Pariante et al, , 2001aMiller et al, 2002), and human peripheral blood mononuclear cells (Vedder et al, 1999). However, reduced GR function in vitro by antidepressants has also been described (Pariante et al, 1997(Pariante et al, , 2001aBudziszewska et al, 2000;Miller et al, 2002).…”