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Chronic treatment with AMPA receptor potentiator Org 26576 increases neuronal cell proliferation and survival in adult rodent hippocampus

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Abstract

Rationale

Currently available antidepressants upregulate hippocampal neurogenesis and prefrontal gliogenesis after chronic administration, which could block or reverse the effects of stress. Allosteric α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators (ARPs), which have novel targets compared to current antidepressants, have been shown to have antidepressant properties in neurogenic and behavioral models.

Objectives

This study analyzed the effect of the ARP Org 26576 on the proliferation, survival, and differentiation of neurons and glia in the hippocampus and prelimbic cortex of adult rats.

Materials and methods

Male Sprague-Dawley rats received acute (single day) or chronic (21 day) twice-daily intraperitoneal injections of Org 26576 (1–10 mg/kg). Bromodeoxyuridine (BrdU) immunohistochemistry was conducted 24 h or 28 days after the last drug injection for the analysis of cell proliferation or survival, respectively. Confocal immunofluorescence analysis was used to determine the phenotype of surviving cells.

Results

Acute administration of Org 26576 did not increase neuronal cell proliferation. However, chronic administration of Org 26576 increased progenitor cell proliferation in dentate gyrus (~40%) and in prelimbic cortex (~35%) at the 10-mg/kg dosage. Cells born in response to chronic Org 26576 in dentate gyrus exhibited increased rates of survival (~30%) with the majority of surviving cells expressing a neuronal phenotype.

Conclusion

Findings suggest that Org 26576 may have antidepressant properties, which may be attributed, in part, to upregulation of hippocampal neurogenesis and prelimbic cell proliferation.

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References

  • Alt A, Nisenbaum ES, Bleakman D, Witkin JM (2006) A role for AMPA receptors in mood disorders. Biochem Pharmacol 71:1273–1288

    Article  PubMed  CAS  Google Scholar 

  • Bai F, Li X, Clay M, Lindstrom T, Skolnick P (2001) Intra- and interstrain differences in models of “behavioral despair”. Pharmacol Biochem Behav 70:187–192

    Article  PubMed  CAS  Google Scholar 

  • Bai F, Bergeron M, Nelson DL (2003) Chronic AMPA receptor potentiator (LY451646) treatment increases cell proliferation in adult rat hippocampus. Neuropharmacology 44:1013–1021

    Article  PubMed  CAS  Google Scholar 

  • Banasr M, Duman RS (2007) Regulation of neurogenesis and gliogenesis by stress and antidepressant treatment. CNS Neurol Disord Drug Targets 6:311–320

    Article  PubMed  CAS  Google Scholar 

  • Banasr M, Duman RS (2008) Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry 64:863–870

    Article  PubMed  Google Scholar 

  • Banasr M, Valentine GW, Li XY, Gourley SL, Taylor JR, Duman RS (2007) Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat. Biol Psychiatry 62:496–504

    Article  PubMed  CAS  Google Scholar 

  • Bleakman D, Alt A, Witkin JM (2007) AMPA receptors in the therapeutic management of depression. CNS Neurol Disord Drug Targets 6:117–126

    Article  PubMed  CAS  Google Scholar 

  • Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall I (2002) Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Arch Gen Psychiatry 58:545–553

    Article  Google Scholar 

  • Drevets WC, Price JL, Simpson JR, Todd RF, Reich T, Vannier M (1997) Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386:824–827

    Article  PubMed  CAS  Google Scholar 

  • Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127

    Article  PubMed  CAS  Google Scholar 

  • Duman RS, Nakagawa S, Malberg J (2001) Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology 25:836–844

    Article  PubMed  CAS  Google Scholar 

  • Erdemli G, Smith LH, Sammons M, Jeggo R, Shahid M (2007) Org 26576, a novel positive allosteric modulator, potentiates AMPA receptor responses in hippocampal neurons. J Psychopharmacology 21:A51

    Google Scholar 

  • Heninger GR, Delgado PL, Charney DS (1996) The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion studies in humans. Pharmacopsychiatry 29:2–11

    Article  PubMed  CAS  Google Scholar 

  • Holick KA, Lee DC, Hen R, Dulawa SC (2008) Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology 33:406–417

    Article  PubMed  CAS  Google Scholar 

  • Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM (2005) Mechanism of positive allosteric modulators acting on AMPA receptors. J Neurosci 25:9027–9036

    Article  PubMed  CAS  Google Scholar 

  • Jordan GR, McCulloch J, Shahid M, Hill DR, Henry B, Horsburgh K (2005) Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxygluoce autoradiography. Neuropharmacology 49:254–264

    Article  PubMed  CAS  Google Scholar 

  • Kessler RC, Berglund P, Demler O, Jin R, Koretz R, Merikangas KR, Rush AJ, Walters EE, Wang PS (2003) The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). J Am Med Assoc 289:3095–3105

    Article  Google Scholar 

  • Kodama M, Fujioka T, Duman RS (2004) Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol Psychiatry 56:570–580

    Article  PubMed  CAS  Google Scholar 

  • Lauterborn JC, Lynch G, Vanderklish P, Arai A, Gall CM (2000) Positive modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J Neurosci 20:8–21

    PubMed  CAS  Google Scholar 

  • Legutko B, Li X, Skolnick P (2001) Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor potentiator. Neuropharmacology 40:1019–1027

    Article  PubMed  CAS  Google Scholar 

  • Li X, Witkin JM, Need AB, Skolnick P (2003) Enhancement of antidepressant potency by a potentiator of AMPA receptors. Cell Mol Neurobiol 23:419–430

    Article  PubMed  CAS  Google Scholar 

  • Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ (2006) Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 367:1747–1757

    Article  PubMed  Google Scholar 

  • Mackowiak M, O’Neill MJ, Hicks CA, Bleakman D, Skolnick P (2002) An AMPA receptor potentiator modulates hippocampal expression of BDNF: an in vivo study. Neuropharmacology 43:1–10

    Article  PubMed  CAS  Google Scholar 

  • Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK (2008) Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 63:349–352

    Article  PubMed  CAS  Google Scholar 

  • Malberg J, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult hippocampus. J Neurosci 20:9104–9110

    PubMed  CAS  Google Scholar 

  • Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002–2030. PLoS Med 3:2011–2030

    Article  Google Scholar 

  • Mathew SJ, Manji HK, Charney DS (2008) Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology 33:2080–2092

    Article  PubMed  CAS  Google Scholar 

  • Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM (2002) Neurobiology of depression. Neuron 34:13–25

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic, New York

    Google Scholar 

  • Sahay A, Hen R (2007) Adult hippocampal neurogenesis in depression. Nature Neuroscience 10:1110–1115

    Article  PubMed  CAS  Google Scholar 

  • Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub M, Lee J, Duman RS, Arancio O, Belzung C, Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effect of antidepressants. Science 301:805–809

    Article  PubMed  CAS  Google Scholar 

  • Segi-Nishida E, Warner-Schmidt JL, Duman RS (2008) Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus. Proc Natl Acad Sci U S A 105:11352–11357

    Article  PubMed  CAS  Google Scholar 

  • Staubli U, Perez Y, Xu FB, Rogers G, Ingvar M, Stone-Elander S, Lynch G (1994) Centrally active modulators of glutamate receptors facilitate the induction of long-term potentiation in vivo. Proc Natl Acad Sci 91:11158–11162

    Article  PubMed  CAS  Google Scholar 

  • van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034

    Article  PubMed  Google Scholar 

  • Warner-Schmidt JL, Duman RS (2007) VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc Natl Acad Sci U S A 104:4647–4652

    Article  PubMed  CAS  Google Scholar 

  • Zarate CA Jr, Manji HK (2008) The role of AMPA receptor modulation in the treatment of neuropsychiatric diseases. Exp Neurol 211:7–10

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Funding was provided through a grant from Schering-Plough.

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Authors and Affiliations

  1. Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, CT, 06508, USA

    Xiaowei W. Su, Xiao-Yuan Li, Mounira Banasr & Ronald S. Duman

  2. Department of Psychiatry, Mount Sinai School of Medicine, New York City, NY, 10029, USA

    Ja Wook Koo

  3. Department of Pharmacology, Schering-Plough, Newhouse, Lanarkshire, UK

    Mohammed Shahid & Brian Henry

Authors
  1. Xiaowei W. Su
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  2. Xiao-Yuan Li
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  3. Mounira Banasr
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  4. Ja Wook Koo
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  5. Mohammed Shahid
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  6. Brian Henry
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  7. Ronald S. Duman
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Correspondence to Ronald S. Duman.

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Su, X.W., Li, XY., Banasr, M. et al. Chronic treatment with AMPA receptor potentiator Org 26576 increases neuronal cell proliferation and survival in adult rodent hippocampus. Psychopharmacology 206, 215–222 (2009). https://doi.org/10.1007/s00213-009-1598-0

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  • DOI: https://doi.org/10.1007/s00213-009-1598-0

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