Differential and Converging Molecular Mechanisms of Antidepressants’ Action in the Hippocampal Dentate Gyrus
Open accessAbstract
Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited, and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine, and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine, and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine that activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms.
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Adult cytogenesis (neurogenesis and gliogenesis) and morphological changes in the hippocampus are altered by chronic stress and reverted by antidepressants.
“neuroplastic events, including adult cytogenesis (neurogenesis9, 10, 11 and gliogenesis12) and morphological changes, are described to be altered by chronic stress and reverted by antidepressants (ADs).13, 14”
From Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression (2017) · cites this paper as [14]
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References 59 · Cited by 57
- Authors
- Patrício, P., Mateus-Pinheiro, A., Irmler, M., Alves, N. D., Machado-Santos, A. R., Morais, M., Correia, J. S., Korostynski, M., Piechota, M., Stoffel, R., Beckers, J., Bessa, J. M., Almeida, O. F., Sousa, N., & Pinto, L.
- Affiliations
- University of Minho (PT)
- Helmholtz Munich (DE)
- Maj Institute of Pharmacology (PL)
- Max Planck Institute of Psychiatry (DE)
- Corresponding author
- Sousa, Nuno
- Pinto, Luísa
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2014-07-18
- Volume
- 40
- Issue
- 2
- Pages
- 338-349
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4443946
- OpenAlex
- W2060542243
- Cited by
- 57
- References
- 59
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 5
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- antidepressants, dentate gyrus, major depressive disorder, chronic unpredictable mild stress, fluoxetine, imipramine, tianeptine, agomelatine, neuroplasticity, pro-inflammatory genes, oligodendrocytes, cytoprotection, gene expression
- MeSH terms
- Acetamides, Animals, Antidepressive Agents, Chronic Disease, Depressive Disorder, Disease Models, Animal, Fluoxetine, Imipramine, Male, Naphthalenes, Neurons, Random Allocation, Stress, Psychological, Thiazepines, Gene Expression, Rats, Wistar, Dentate Gyrus, Uncertainty
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