Stress-Induced Changes of Hippocampal NMDA Receptors: Modulation by Duloxetine Treatment
Open accessAbstract
It is now well established that the glutamatergic system contributes to the pathophysiology of depression. Exposure to stress, a major precipitating factor for depression, enhances glutamate release that can contribute to structural abnormalities observed in the brain of depressed subjects. On the other hand, it has been demonstrated that NMDA antagonists, like ketamine, exert an antidepressant effect at preclinical and clinical levels. On these bases, the purpose of our study was to investigate whether chronic mild stress is associated with specific alterations of the NMDA receptor complex, in adult rats, and to establish whether concomitant antidepressant treatment could normalize such deficits. We found that chronic stress increases the expression of the obligatory GluN1 subunit, as well as of the accessory subunits GluN2A and GluN2B at transcriptional and translational levels, particularly in the ventral hippocampus. Concomitant treatment with the antidepressant duloxetine was able to normalize the increase of glutamatergic receptor subunit expression, and correct the changes in receptor phosphorylation produced by stress exposure. Our data suggest that prolonged stress, a condition that has etiologic relevance for depression, may enhance glutamate activity through post-synaptic mechanisms, by regulating NMDA receptors, and that antidepressants may in part normalize such changes. Our results provide support to the notion that antidepressants may exert their activity in the long-term also via modulation of the glutamatergic synapse.
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Chronic treatment with an SNRI or a tricyclic antidepressant downregulates NMDA receptor sensitivity in the cerebral cortex and frontal cortex and hippocampus.
“chronic treatment with an SNRI or a tricyclic antidepressant downregulates NMDA receptor sensitivity in the cerebral cortex (Nowak et al, 1993) and frontal cortex and hippocampus (Calabrese et al, 2012; Bobula and Hess, 2008).”
From D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial (2014) · cites this paper as Calabrese et al, 2012
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- Authors
- Calabrese, F., Guidotti, G., Molteni, R., Racagni, G., Mancini, M., & Riva, M. A.
- Affiliations
- University of Milan (IT)
- Eli Lilly (Italy) (IT)
- Corresponding author
- Riva, Marco Andrea
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-05-29
- Volume
- 7
- Issue
- 5
- Pages
- e37916
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3362535
- OpenAlex
- W2057374715
- Cited by
- 107
- References
- 42
- Citations by year
- 2025: 2 · 2024: 12 · 2023: 5 · 2022: 5 · 2021: 14 · 2020: 11 · 2019: 8 · 2018: 8 · 2017: 9 · 2016: 8 · 2015: 10 · 2014: 9 · 2013: 4 · 2012: 2
- FWCI
- 5.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Regione Lombardia
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- NMDA receptor, chronic mild stress, depression, duloxetine, ventral hippocampus, GluN1 subunit, GluN2A, GluN2B, receptor subunit expression, receptor phosphorylation, glutamatergic synapses, antidepressant mechanism, ketamine
- MeSH terms
- Duloxetine Hydrochloride, Animals, Antidepressive Agents, Anxiety, Behavior, Animal, Gene Expression Regulation, Hippocampus, Male, Memory, Phosphorylation, Spatial Behavior, Stress, Psychological, Thiophenes, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Prefrontal Cortex, Protein Subunits, Rats
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