Cited by 200Stress Responses and CortisolTreatment of Major DepressionNeurotransmitter Receptor Influence on Behavior

Glucocorticoid Receptor and FKBP5 Expression Is Altered Following Exposure to Chronic Stress: Modulation by Antidepressant Treatment

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Guidotti, Gianluigi, Calabrese, Francesca, Anacker, Christoph, Racagni, Giorgio, Pariante, Carmine M, Riva, Marco A·2013·Neuropsychopharmacology

Abstract

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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  1. Paxinos G, Watson C. The Rat Brain in Stereotaxis Coordinates. Academic Press: New York; 1996. [Google Scholar]

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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
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
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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