Vascular Endothelial Growth Factor Signaling is Required for the Behavioral Actions of Antidepressant Treatment: Pharmacological and Cellular Characterization
Open accessAbstract
This study extends earlier work on the role of vascular endothelial growth factor (VEGF) in the actions of antidepressant treatment in two key areas. First, by determining the requirement for VEGF in the actions of a 5-HT selective reuptake inhibitor (SSRI), fluoxetine in behavioral models of depression/antidepressant response; and second, by examining the role of the 5-HT1A receptor subtype in the regulation of VEGF, and the cellular localization of antidepressant regulation of VEGF expression. The results show that pharmacological inhibition of VEGF receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress. Infusions of SU5416 or SU1498, two structurally dissimilar inhibitors of VEGF-Flk-1 receptor signaling, block the antidepressant effects of fluoxetine on sucrose preference, immobility in the forced swim test, and latency to feed in the novelty suppressed feeding paradigm. We also show that activation of 5-HT1A receptors is sufficient to induce VEGF expression and that a 5-HT1A antagonist blocks both the increase in VEGF and behavioral effects induced by fluoxetine. Finally, double labeling studies show that chronic fluoxetine administration increases VEGF expression in both neurons and endothelial cells in the hippocampus. Taken together these studies show that VEGF is necessary for the behavioral effects of the SSRI fluoxetine, as well as norepinephrine selective reuptake inhibitor, and that these effects may be mediated by 5-HT1A receptors located on neurons and endothelial cells.
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VEGF seems to be required for the behavioral action of various antidepressant drugs in rodent models of depression.
“In a similar manner, VEGF also seems to be required for the behavioral action of various antidepressant drugs in rodent models of depression (Greene et al. 2009; Sun et al. 2012; Warner-Schmidt and Duman 2007; Warner-Schmidt and Duman 2008).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Greene et al. 2009
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“Novelty suppression of feeding tests are increasingly used as measures of anxiety (Bilkei-Gorzo et al., 2002; Catts et al., 2008; Greene et al., 2009; Leuner et al., 2010) and have been readily adapted to birds (Kelly et al., 2011).”
- Authors
- Greene, J., Banasr, M., Lee, B., Warner-Schmidt, J., & Duman, R. S.
- Affiliations
- Yale University (US)
- Corresponding author
- Duman, Ronald S
- Venue
- Neuropsychopharmacology
- Published
- 2009-06-24
- Volume
- 34
- Issue
- 11
- Pages
- 2459-2468
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3694572
- OpenAlex
- W1965815632
- Cited by
- 143
- References
- 53
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 7 · 2019: 5 · 2018: 9 · 2017: 5 · 2016: 12 · 2015: 10 · 2014: 9 · 2013: 19 · 2012: 19
- FWCI
- 10.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service (2 PO1 MH25642, MH45481)
- National Institute of Mental Health (2-PO1-MH25642, MH-45481, R37MH045481, P01MH025642, R01MH045481)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- vascular endothelial growth factor, VEGF signaling, antidepressant effects, fluoxetine, selective serotonin reuptake inhibitors, 5-HT1A receptor, depression, chronic unpredictable mild stress, VEGF receptor inhibition, SU5416, SU1498, sucrose preference, forced swim test, novelty-suppressed feeding, hippocampus, endothelial cells, norepinephrine reuptake inhibitors
- MeSH terms
- Animals, Antidepressive Agents, Depression, Fluoxetine, Hippocampus, Male, Neurons, Neuropsychological Tests, Random Allocation, Stress, Psychological, Signal Transduction, Rats, Sprague-Dawley, Selective Serotonin Reuptake Inhibitors, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Endothelial Cells, Receptor, Serotonin, 5-HT1A, Rats, Serotonin 5-HT1 Receptor Antagonists
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