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Cited by 1,267Neurogenesis and neuroplasticity mechanismsTreatment of Major DepressionStress Responses and Cortisol

Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression

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David, Denis J., Samuels, Benjamin Adam, Rainer, Quentin, Wang, Jing-Wen, Marsteller, Douglas, Mendez, Indira, Drew, Michael, Craig, Douglas A. +8 more·2009·Neuron
DOI 10.1016/j.neuron.2009.04.017PMC PMC2759281
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Abstract

Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.

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Crossref · 10.1016/j.neuron.2009.04.017

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  • Not all antidepressant actions require neurogenesis and depletion of neurogenesis in itself is not directly causing anxiety/depression-like behavior.

    “There is however evidence that not all the antidepressant actions require neurogenesis and that the depletion of neurogenesis in itself is not directly causing anxiety/depression-like behavior (David et al., 2009;Henn and Vollmayr, 2004), a fact that may be partially reconciled by the existence of extra-neurogenic actions of antidepressants exerted on neural plasticity (see below Section 6”

    From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as David et al., 2009

    The Discussion and Results report that fluoxetine retained antidepressant-like effects in the open-field and forced-swim tests after hippocampal neurogenesis was ablated. The Results also say ablation did not change corticosterone-induced anxiety/depression-like effects, but they do not establish that depletion by itself cannot cause such behavior in otherwise untreated mice. No page numbers are available in our copy. (LLM, conf=0.82)

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  • Ablation of neurogenesis does not result in anxiety/depression-like symptoms.

    “although the ablation of neurogenesis does not result in anxiety/depression-like symptoms (according to David et al., 2009)”

    From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as David et al., 2009

    The Results section (page unavailable) reports that complete loss of hippocampal neurogenesis did not change corticosterone-induced anxiety/depression-like behavior in the open-field test. That supports a narrower finding, but the paper does not establish the broader claim that ablation by itself does not produce anxiety/depression-like symptoms. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Adult hippocampal neurogenesis is required for the therapeutic action of antidepressants.

    “Adult hippocampal neurogenesis was proposed to be required for the therapeutic action of antidepressants (David et al. 2009; Djavadian 2004; Klempin et al. 2013; Sahay and Hen 2007; Santarelli et al. 2003).”

    From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as David et al. 2009

    The Discussion (“Neurogenesis-dependent and independent mechanisms”; page not provided) says hippocampal neurogenesis is required for some antidepressant effects and reports that it was necessary for fluoxetine’s effect in one mouse behavioral test. It also reports antidepressant-like effects in other tests that persisted after neurogenesis was ablated, so the proposed requirement does not extend to antidepressant action generally. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Negative results of chronic administration were reported and neurogenesis-independent mechanisms of fluoxetine action were described.

    “Negative results of chronic administration were reported (Marlatt et al., 2013) and neurogenesis-independent mechanisms of fluoxetine action were described (David et al., 2009).”

    From Serotonin and neuroplasticity – Links between molecular, functional and structural pathophysiology in depression (2017) · cites this paper as David et al., 2009

  • A few studies provide evidence that absence of neurogenesis elicits depressive-like symptoms in rodents, but most studies find that absent neurogenesis is not sufficient to induce a depressive phenotype, although it is required in mice for the behavioral effects of antidepressants.

    “A few studies provide evidence that the absence of neurogenesis elicits depressive like symptoms in rodents123, 124, but most studies find that absent neurogenesis is not sufficient to induce a depressive phenotype125 although it is required in mice for the behavioral effects of antidepressants118, 126.”

    From Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications (2022) · cites this paper as [118]

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Authors
David, D. J., Samuels, B. A., Rainer, Q., Wang, J.-W., Marsteller, D., Mendez, I., Drew, M., Craig, D. A., Guiard, B. P., Guilloux, J.-P., Artymyshyn, R. P., Gardier, A. M., Gerald, C., Antonijevic, I. A., Leonardo, E. D., & Hen, R.
Affiliations
  • Université Paris-Sud (FR)
  • Columbia University (US)
  • Lundbeck (United States) (US)
Corresponding author
  • David, Denis J.
  • Hen, René
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2009-05
Volume
62
Issue
4
Pages
479-493
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2009.04.017
PMC
PMC2759281
OpenAlex
W2014099101
Cited by
1,267
References
63
Citations by year
2026: 26 · 2025: 51 · 2024: 47 · 2023: 69 · 2022: 63 · 2021: 79 · 2020: 66 · 2019: 91 · 2018: 72 · 2017: 78 · 2016: 87 · 2015: 93 · 2014: 104 · 2013: 99 · 2012: 80
FWCI
24.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (R37MH068542, K08MH076083, K99MH083943, R01MH068542)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD055165, 5-T32HD55165-02)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
fluoxetine, hippocampal neurogenesis, chronic corticosterone, anxiety, depression, antidepressant mechanism, X-ray irradiation, hypothalamus, β-arrestin2, β-arrestin signaling, candidate genes, mood disorders
MeSH terms
beta-Arrestins, beta-Arrestin 2, Doublecortin Domain Proteins, Analysis of Variance, Animals, Anxiety, Bromodeoxyuridine, Cell Survival, Corticosterone, Depression, Disease Models, Animal, Drug Administration Schedule, Exploratory Behavior, Feeding Behavior, Fluoxetine, Gene Expression Regulation, Hippocampus, Hypothalamus, Male, Mice, Inbred C57BL, Microtubule-Associated Proteins, Neuropeptides, Radiation, Reaction Time, RNA, Messenger, Mice, Knockout, Antidepressive Agents, Second-Generation, Arrestins, Cell Proliferation, Mice, GTP-Binding Protein alpha Subunit, Gi2, Neurogenesis

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