Do antidepressants regulate how cortisol affects the brain?

Pariante, Carmine M.; Thomas, Sarah A.; Lovestone, Simon; Makoff, Andrew; Kerwin, Robert W.

doi:10.1016/j.psyneuen.2003.10.009

Cited by 194Stress Responses and CortisolTreatment of Major DepressionAdrenal Hormones and Disorders

Do antidepressants regulate how cortisol affects the brain?

Pariante, Carmine M., Thomas, Sarah A., Lovestone, Simon, Makoff, Andrew, Kerwin, Robert W.·2004·Psychoneuroendocrinology

DOI 10.1016/j.psyneuen.2003.10.009

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Abstract

Although the effects of antidepressants on glucocorticoid hormones and their receptors are relevant for the therapeutic action of these drugs, the molecular mechanisms underlying these effects are unclear. Studies in depressed patients, animals and cellular models have demonstrated that antidepressants increase glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression and function; this, in turn, is associated with enhanced negative feedback by endogenous glucocorticoids, and thus with reduced resting and stimulated hypothalamic-pituitary-adrenal (HPA) axis activity. In a series of studies conducted over the last few years, we have shown that antidepressants modulate GR function in vitro by inhibiting membrane steroid transporters that regulate the intracellular concentration of glucocorticoids. In this paper, we will review the effects of membrane steroid transporters and antidepressants on corticosteroid receptors. We will then present our unpublished data on GR live microscopy in vitro, showing that ligand-induced translocation of the GR starts within 30 seconds and is completed within minutes. Furthermore, we will present our new data using an in situ brain perfusion model in anaesthetised guinea-pigs, showing that entry of cortisol to the brain of these animals is limited at the blood-brain barrier (BBB). Finally, we will present a comprehensive discussion of our published findings on the effects of chemically unrelated antidepressants on membrane steroid transporters, in mouse fibroblasts and rat cortical neurones. We propose that antidepressants in humans could inhibit steroid transporters localised on the BBB and in neurones, like the multidrug resistance p-glycoprotein, and thus increase the access of cortisol to the brain and the glucocorticoid-mediated negative feedback on the HPA axis. Enhanced cortisol action in the brain might prove to be a successful approach to maximise therapeutic antidepressant effects.

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Authors: Pariante, C. M., Thomas, S. A., Lovestone, S., Makoff, A., & Kerwin, R. W.
Affiliations: King's College London (GB)
Corresponding author: Pariante, Carmine M.
ORCID: Pariante, Carmine M.
Thomas, Sarah A.
Lovestone, Simon
Venue: Psychoneuroendocrinology
Publisher: Elsevier BV
Published: 2004-05
Volume: 29
Issue: 4
Pages: 423-447
ISSN: 0306-4530 (ISSN-L)
DOI: 10.1016/j.psyneuen.2003.10.009
OpenAlex: W2156505367
Cited by: 194
References: 130
Citations by year: 2026: 3 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 7 · 2017: 7 · 2016: 6 · 2015: 5 · 2014: 10 · 2013: 11 · 2012: 12
FWCI: 9.00
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Psychoneuroendocrinology (publishedVersion)
PubMed (publishedVersion)
Research Portal (King's College London) (submittedVersion)
Funders: Georgetown University
National Alliance for Research on Schizophrenia and Depression
Wellcome Trust
Psychiatry Research Trust
Medical Research Council
Topics: Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords: antidepressants, glucocorticoid receptor, mineralocorticoid receptor, cortisol, blood-brain barrier, hypothalamic-pituitary-adrenal axis, negative feedback, receptor translocation, cortical neurons, depression
MeSH terms: Animals, Antidepressive Agents, Blood-Brain Barrier, Brain, Brain Chemistry, Guinea Pigs, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Receptors, Steroid, Feedback, Physiological, Membrane Transport Proteins, Mice, Rats, In Vitro Techniques

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Do antidepressants regulate how cortisol affects the brain?

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