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Antidepressant drugs inhibit glucocorticoid receptor‐mediated gene transcription – a possible mechanism
Author(s) -
Budziszewska Bogusława,
JaworskaFeil Lucylla,
Kajta Małgorzata,
Lasoń Władysław
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703445
Subject(s) - imipramine , glucocorticoid receptor , desipramine , mianserin , protein kinase c , pharmacology , glucocorticoid , chemistry , creb , protein kinase a , endocrinology , medicine , antidepressant , biology , receptor , transcription factor , kinase , serotonin , gene , biochemistry , alternative medicine , pathology , hippocampus
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), Ca 2+ /calmodulin‐dependent protein kinase (CaMK) and antagonists of the L‐type Ca 2+ 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: 10.1038/sj.bjp.0703445