Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters.
1. Previous data demonstrate that the tricyclic antidepressant, desipramine, induces glucocorticoid receptor (GR) translocation from the cytoplasm to the nucleus in L929 cells and increases dexamethasone-induced GR-mediated gene transcription in L929 cells stably transfected with the mouse mammary tumour virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter gene (LMCAT cells) (Pariante et al., 1997). 2. To extend these findings, the present study has investigated the effects of 24 h coincubation of LMCAT cells with dexamethasone and amitriptyline, clomipramine, paroxetine, citalopram or fluoxetine. 3. All antidepressants, except fluoxetine, enhanced GR-mediated gene transcription, with clomipramine having the greatest effect (10 fold increase). Twenty-four hours coincubation of cells with desipramine, clomipramine or paroxetine, also enhanced GR function in the presence of cortisol, but not of corticosterone. 4. It is proposed that these effects are due to the antidepressants inhibiting the L929 membrane steroid transporter, which actively extrudes dexamethasone and cortisol from the cell, but not corticosterone. This is further confirmed by the fact that clomipramine failed to enhance GR-mediated gene transcription in the presence of dexamethasone when the membrane steroid transporter was blocked by verapamil. 5. The membrane steroid transporters that regulate access of glucocorticoids to the brain in vivo, like the multiple drug resistance p-glycoprotein, could be a fundamental target for antidepressant action.
Pariante
C M
CM
Section of Clinical Neuropharmacology, Institute of Psychiatry, King's College London, London SE5 8AF. spjucmp@iop.kcl.ac.uk
Makoff
A
A
Lovestone
S
S
Feroli
S
S
Heyden
A
A
Miller
A H
AH
Kerwin
R W
RW
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D002997:Clomipramine / Q000494:pharmacology; D003345:Corticosterone / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D006854:Hydrocortisone / Q000494:pharmacology; D066298:In Vitro Techniques; D017374:Paroxetine / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology*
D000928:Antidepressive Agents; D002121:Calcium Channel Blockers; D015500:Chloramphenicol O-Acetyltransferase; D002997:Clomipramine; D003345:Corticosterone; D003907:Dexamethasone; D005938:Glucocorticoids; D006854:Hydrocortisone; D017374:Paroxetine; D011965:Receptors, Glucocorticoid; D017367:Selective Serotonin Reuptake Inhibitors; D014700:Verapamil