Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters

C M Pariante, A Makoff, S Lovestone, S Feroli, A Heyden, A H Miller, R W Kerwin

Research output: Contribution to journalArticlepeer-review

143 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1335 - 1343
Number of pages9
JournalBritish Journal of Pharmacology
Volume134
Issue number6
DOIs
Publication statusPublished - 2001

Fingerprint

Dive into the research topics of 'Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters'. Together they form a unique fingerprint.

Cite this