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Research ArticleNEUROPHARMACOLOGY

Sex-Specific Effects of Chronic Fluoxetine Treatment on Neuroplasticity and Pharmacokinetics in Mice

Georgia E. Hodes, Tiffany E. Hill-Smith, Raymond F. Suckow, Thomas B. Cooper and Irwin Lucki
Journal of Pharmacology and Experimental Therapeutics January 2010, 332 (1) 266-273; DOI: https://doi.org/10.1124/jpet.109.158717
Georgia E. Hodes
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Tiffany E. Hill-Smith
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Raymond F. Suckow
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Thomas B. Cooper
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Irwin Lucki
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Abstract

Neurogenesis is a mechanism through which antidepressants may produce therapeutic effects. There is a dearth of information regarding the effects of antidepressants on neurogenesis and neurotrophin mobilization in females. This study examined sex differences in the alteration of cell proliferation and survival in multiple regions of the brain. Additional experiments examined brain-derived neurotrophic factor (BDNF) levels and pharmacokinetics of fluoxetine to determine whether they mediate sex differences. MRL/MpJ mice were treated with fluoxetine (5 and 10 mg/kg b.i.d.) for 21 days and received injections of 5-bromo-2′-deoxyuridine (200 mg/kg) to measure DNA synthesis. In the hippocampus, fluoxetine increased cell proliferation at both doses; females treated with 10 mg/kg produced more new cells than males. Fluoxetine did not alter survival in males, but 10 mg/kg reduced survival in females. In the frontal cortex, fluoxetine increased cell proliferation and survival in males treated with 10 mg/kg. In the cerebellum and amygdala, 10 mg/kg fluoxetine increased cell proliferation in both sexes but did not alter the incorporation of the new cells. Fluoxetine increased BDNF levels in the hippocampus of both sexes. BDNF levels correlated with cell proliferation in males but not females. Brain and plasma levels indicated that females metabolized fluoxetine faster than males and produced more of the metabolite norfluoxetine. These data suggest that fluoxetine acts on multiple areas of the brain to increase cell proliferation, and the pattern of activation differs between males and females. Sex-specific effects of fluoxetine on neurotrophin mobilization and pharmacokinetics may contribute to these differences in neural plasticity.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Mental Health [Grants MH072832 and MH014654].

  • Parts of this work were previously presented as a poster as follows: Hodes GE and Lucki I (2008) Females and fluoxetine: effects of antidepressants on the brain and behavior. Society for Neuroscience Annual Meeting; 2008 Nov 15–19; Washington, DC. Society for Neuroscience, Washington, DC.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.109.158717

  • ABBREVIATIONS:

    BDNF
    brain-derived neurotrophic factor
    BrdU
    5-bromo-2-deoxyuridine
    7-AAD
    7-aminoactinomycin D
    FBS
    fetal bovine serum
    FITC
    fluorescein isothiocyanate
    PBS
    phosphate-buffered saline.

    • Received July 8, 2009.
    • Accepted October 14, 2009.
  • © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 332 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 332, Issue 1
1 Jan 2010
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Research ArticleNEUROPHARMACOLOGY

Sex-Specific Effects of Chronic Fluoxetine Treatment on Neuroplasticity and Pharmacokinetics in Mice

Georgia E. Hodes, Tiffany E. Hill-Smith, Raymond F. Suckow, Thomas B. Cooper and Irwin Lucki
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 266-273; DOI: https://doi.org/10.1124/jpet.109.158717

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Research ArticleNEUROPHARMACOLOGY

Sex-Specific Effects of Chronic Fluoxetine Treatment on Neuroplasticity and Pharmacokinetics in Mice

Georgia E. Hodes, Tiffany E. Hill-Smith, Raymond F. Suckow, Thomas B. Cooper and Irwin Lucki
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 266-273; DOI: https://doi.org/10.1124/jpet.109.158717
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