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), Ca(2+)/calmodulin-dependent protein kinase (CaMK) and antagonists of the L-type Ca(2+) 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 (an activator of PKC) 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.
Budziszewska
B
B
Department of Endocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Jaworska-Feil
L
L
Kajta
M
M
Lasoń
W
W
D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D015500:Chloramphenicol O-Acetyltransferase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D003345:Corticosterone / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007099:Imipramine / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008559:Memantine / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000502:physiology*; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D000928:Antidepressive Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D004963:Estrenes; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D013449:Sulfonamides; D013873:Thionucleotides; C024357:corticosterone receptor; D013629:Tamoxifen; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C016957:adenosine-3',5'-cyclic phosphorothioate; D015735:Mifepristone; C033772:N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide; D000547:Amantadine; D000242:Cyclic AMP; D015500:Chloramphenicol O-Acetyltransferase; D010738:Type C Phospholipases; D018021:Lithium Chloride; D006152:Cyclic GMP; D003042:Cocaine; D007099:Imipramine; D008559:Memantine; D003345:Corticosterone