TY - JOUR
T1 - Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters
AU - Pariante, C M
AU - Makoff, A
AU - Lovestone, S
AU - Feroli, S
AU - Heyden, A
AU - Miller, A H
AU - Kerwin, R W
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0035197083&partnerID=8YFLogxK
U2 - 10.1038/sj.bjp.0704368
DO - 10.1038/sj.bjp.0704368
M3 - Article
SN - 1476-5381
VL - 134
SP - 1335
EP - 1343
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 6
ER -