Glucocorticoid Receptor and FKBP5 Expression Is Altered Following Exposure to Chronic Stress: Modulation by Antidepressant Treatment
Open accessAbstract
Major depression is thought to originate from the interaction between susceptibility genes and adverse environmental events, in particular stress. The hypothalamus-pituitary-adrenal (HPA) axis is the major system involved in stress response and its dysregulation is an important element in the pathogenesis of depression. The stress response is therefore finely tuned through a series of mechanisms that control the trafficking of glucocorticoid receptors (GRs) to the nucleus, including binding to the chaperone protein FKBP5 and receptor phosphorylation, suggesting that these elements may also be affected under pathologic conditions. On these bases, we investigated FKBP5 and GR expression and phosphorylation in the hippocampus (ventral and dorsal) and in the prefrontal cortex of rats exposed to chronic mild stress (CMS) and we analyzed the effect of a concomitant antidepressant treatment. We found that animals exposed to CMS show increased expression of FKBP5 as well as enhanced cytoplasmic levels of GR, primarily in ventral hippocampus and prefrontal cortex. Chronic treatment with the antidepressant duloxetine is able to normalize such alterations, mainly in the prefrontal cortex. Moreover, we demonstrate that CMS-induced alterations of GR trafficking and transcription may be sustained by changes in receptor phosphorylation, which are also modulated by pharmacological intervention. In summary, while GR-related changes after CMS might be relevant for the depressive phenotype, the ability of antidepressant treatment to correct some of these alterations may contribute to the normalization of HPA axis dysfunctions associated with stress-related disorders.
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Oxidative stress may be involved in FKBP5 functionality due to the interaction between FOXO1, glucocorticoid receptors, and increased levels of psychological stress.
“Similarly, oxidative stress may be involved in FKBP5 functionality due to the interaction between FOXO1 (a transcription factor involved in cell survival and modulated by oxidative stress), glucocorticoid receptors, and increased levels of psychological stress [196].”
From Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches (2016) · cites this paper as [196]
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- Authors
- Guidotti, G., Calabrese, F., Anacker, C., Racagni, G., Pariante, C. M., & Riva, M. A.
- Affiliations
- University of Milan (IT)
- King's College London (GB)
- Corresponding author
- Riva, Marco A
- Venue
- Neuropsychopharmacology
- Published
- 2012-11-21
- Volume
- 38
- Issue
- 4
- Pages
- 616-627
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3572458
- OpenAlex
- W2063379674
- Cited by
- 200
- References
- 49
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 15 · 2023: 9 · 2022: 12 · 2021: 13 · 2020: 7 · 2019: 11 · 2018: 18 · 2017: 19 · 2016: 22 · 2015: 16 · 2014: 22 · 2013: 12 · 2012: 1
- FWCI
- 6.83
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Eli Lilly and Company
- South London and Maudsley NHS Foundation Trust
- National Institute for Health and Care Research
- King's College London
- Regione Lombardia
- Medical Research Council (MR/J002739/1)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- glucocorticoid receptor, FKBP5, chronic mild stress, major depressive disorder, HPA axis dysregulation, receptor trafficking, receptor phosphorylation, antidepressant treatment, duloxetine, hippocampus, prefrontal cortex, stress response
- MeSH terms
- Tacrolimus Binding Protein 5, Animals, Antidepressive Agents, Brain, Chronic Disease, Gene Expression Regulation, Male, Receptors, Glucocorticoid, Stress, Psychological, Treatment Outcome, Rats, Sprague-Dawley, Tacrolimus Binding Proteins, Rats
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