Antidepressant fluoxetine enhances glucocorticoid receptor function in vitro by modulating membrane steroid transporters
Open accessAbstract
Incubation of LMCAT fibroblast cells with antidepressants potentiates glucocorticoid receptor (GR)‐mediated gene transcription in the presence of dexamethasone 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 fluoxetine in the presence of dexamethasone have produced negative results (Pariante et al. (2001). Br. J. Pharmacol., 134, 1335–1343). 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‐glycoprotein activity in Caco‐2 cells. We now find that fluoxetine (1–10 μM) enhances GR‐mediated gene transcription in the presence of dexamethasone and cortisol (+140–170%), but not of corticosterone, and increases the intracellular accumulation of 3 H‐cortisol (+5–15%), but not of 3 H‐corticosterone. Moreover, fluoxetine (10 μM) induces approximately 30% inhibition of PGP activity in Caco‐2 cells. Our results show that fluoxetine, like other antidepressants, inhibits membrane steroid transporters. British Journal of Pharmacology (2003) 139, 1111–1118. doi:10.1038/sj.bjp.0705357
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Antidepressants directly regulate the function of the glucocorticoid receptor (GR).
“an extensive literature, some from our own group, which shows that antidepressants directly regulate the function of the glucocorticoid receptor (GR).18, 19, 20, 21, 22, 23, 24”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [24]
Antidepressants induce GR nuclear translocation and transactivation, at least in part mediated by the cAMP/PKA cascade.
“Studies by us and others have shown that antidepressants also induce GR nuclear translocation and transactivation, which is, at least in part, mediated by the cyclic AMP (cAMP)/protein kinase A (PKA) cascade.21, 22, 23, 24, 30, 31, 32, 33”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [24]
The decrease in GR expression by sertraline probably results from increased GR transactivation.
“probably results from the increased GR transactivation.19, 23, 24”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [24]
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- Authors
- Pariante, C. M., Kim, R. B., Makoff, A., & Kerwin, R. W.
- Affiliations
- King's College London (GB)
- Vanderbilt University (US)
- Corresponding author
- Pariante, Carmine M
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2003-07
- Volume
- 139
- Issue
- 6
- Pages
- 1111-1118
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC1573949
- OpenAlex
- W2065124716
- Cited by
- 89
- References
- 45
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 5 · 2020: 2 · 2019: 3 · 2017: 5 · 2016: 4 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 6
- FWCI
- 2.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (GM31304, P01GM031304)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- fluoxetine, antidepressants, glucocorticoid receptor, P-glycoprotein, multidrug resistance, dexamethasone, cortisol, corticosterone, Caco-2 cells
- MeSH terms
- Animals, Corticosterone, Fluoxetine, Humans, Hydrocortisone, Receptors, Glucocorticoid, Steroids, Antidepressive Agents, Second-Generation, Caco-2 Cells, Membrane Transport Proteins, Membrane Transport Modulators, Mice
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