Antidepressant fluoxetine enhances glucocorticoid receptor function in vitro by modulating membrane steroid transporters.

1 Incubation of LMCAT fibroblast cells with antidepressants potentiates glucocorticoid receptor (GR)-mediated gene transcription in the presence of dexarnethasone and cortisol, but not of corticosterone. We have shown that antidepressants do so by inhibiting the LMCAT cell membrane steroid transporter (which is virtually identical to the multidrug resistance P-glycoprotein) and thus by increasing dexamethasone or cortisol intracellular concentrations. However, previous experiments with the antidepressant Iluoxetine in the presence of dexamethasone have produced negative results (Pariante et al. (2001). Br. J. Pharmacol., 134, l335-l343). 2 We have since re-examined the effects of fluoxetine on GR-mediated gene transcription in the presence of dexamethasone. Moreover, we have examined the effects of fluoxetine on GR-mediated gene transcription in the presence of cortisol and corticosterone, and on the intracellular accumulation of radioactive cortisol and corticosterone. Finally, we have examined the effects of fluoxetine on inhibition of P-giyeoprotein activity in Caco-2 cells. 3 We now find that fluoxetine (1 - 10μM) enhances GR-mediated gene transcription in the presence of dexanlethasone and cortisoi (+140-170%), but not of corticosterone, and increases the intracellular accumulation of ³H-eortisol (+ 5-15%), but not of ³H-corticosterone. Moreover, fluoxetine (10 μM) induces approximately 30% inhibition of PGP activity in Caco-2 cells. 4 Our results show that fluoxetine, like other antidepressants, inhibits membrane steroid transporters. [ABSTRACT FROM AUTHOR]