B. Budziszewska et al., Antidepressant drugs inhibit glucocorticoid receptor-mediated gene transcription - a possible mechanism, BR J PHARM, 130(6), 2000, pp. 1385-1393
1 Antidepressant drugs are known to inhibit some changes evoked by glucocor
ticoids, 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 antidepres
sant 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, amitriptyl
ine, desipramine, fluoxetine, tianeptine, mianserin and moclobemide), but n
ot cocaine, inhibit the corticosterone-induced gene transcription in a conc
entration- and a time-dependent manner.
4 Drugs which are known to augment clinical effects of medication in depres
sed patients (lithium chloride, amantadine, memantine), do not affect the i
nhibitory effects of imipramine on the glucocorticoid receptor (GR)-mediate
d gene transcription. 5 Inhibitors of phospholipase C (PLC), protein kinase
C (PKC), Ca2+/calmodulin-dependent protein kinase (CaMK) and antagonists o
f the L-type Ca2+ channel also inhibit the corticosterone-induced gene tran
scription.
6 Inhibitors of protein kinase A (PKA) and protein kinase G (PKG) are witho
ut 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-indu
ced gene transcription, and that the inhibitory effect of imipramine depend
s partly on the PLC/PKC pathway.