The antidepressant clomipramine regulates cortisol intracellular concentrations and glucocorticoid receptor expression in fibroblasts and rat primary neurones.
Incubation of LMCAT fibroblasts cells with antidepressants potentiates glucocorticoid receptor (GR)-mediated gene transcription in the presence of cortisol, but not of corticosterone. We have suggested that antidepressants do so by inhibiting the LMCAT cells membrane steroid transporter and thus by increasing cortisol intracellular concentrations. We now confirm and extend this model to primary neuronal cultures. Clomipramine, a tricyclic antidepressant, increased the intracellular accumulation of 3H-cortisol, but not 3H-corticosterone, in LMCAT cells (+80%) and primary rat neurones (+20%). The latter finding is the first demonstration that a membrane steroid transporter is present in neurones. Moreover, verapamil, a membrane steroid transporter inhibitor, reduced the effects of clomipramine on the intracellular accumulation of 3H-cortisol in LMCAT cells. Finally, clomipramine also decreased GR expression (whole-cell Western blot) in LMCAT cells (50% reduction) and primary rat neurones (80% reduction). This GR downregulation can explain the reduced GR-mediated gene transcription previously described under experimental conditions that do not elicit the effects on the LMCAT cells steroid transporter. This work further supports the hypothesis that membrane steroid transporters regulating the access of glucocorticoids to the brain in vivo are a fundamental target for antidepressant action.
Pariante
Carmine M
CM
Section of Clinical Neuropharmacology, Institute of Psychiatry, King's College London, London, UK. spjucmp@iop.kcl.ac.uk
Hye
Abdul
A
Williamson
Ritchie
R
Makoff
Andrew
A
Lovestone
Simon
S
Kerwin
Robert W
RW
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002997:Clomipramine / Q000494:pharmacology*; D003345:Corticosterone / Q000378:metabolism; D003720:Densitometry / Q000295:instrumentation / Q000379:methods; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005110:Extracellular Space / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006854:Hydrocortisone / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D014316:Tritium / Q000378:metabolism
D000929:Antidepressive Agents, Tricyclic; D011965:Receptors, Glucocorticoid; D014316:Tritium; D002997:Clomipramine; D003345:Corticosterone; D006854:Hydrocortisone