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Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole

Molecular Psychiatry volume 15, pages 501–511 (2010)Cite this article

Abstract

Growing evidence indicates that glia pathology and amino-acid neurotransmitter system abnormalities contribute to the pathophysiology and possibly the pathogenesis of major depressive disorder. This study investigates changes in glial function occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Furthermore, we analyzed the effects of riluzole, a Food and Drug Administration-approved drug for the treatment of amyotrophic laterosclerosis, known to modulate glutamate release and facilate glutamate uptake, on CUS-induced glial dysfunction and depressive-like behaviors. We provide the first experimental evidence that chronic stress impairs cortical glial function. Animals exposed to CUS and showing behavioral deficits in sucrose preference and active avoidance exhibited significant decreases in 13C-acetate metabolism reflecting glial cell metabolism, and glial fibrillary associated protein (GFAP) mRNA expression in the PFC. The cellular, metabolic and behavioral alterations induced by CUS were reversed and/or blocked by chronic treatment with the glutamate-modulating drug riluzole. The beneficial effects of riluzole on CUS-induced anhedonia and helplessness demonstrate the antidepressant action of riluzole in rodents. Riluzole treatment also reversed CUS-induced reductions in glial metabolism and GFAP mRNA expression. Our results are consistent with recent open-label clinical trials showing the drug's effect in mood and anxiety disorders. This study provides further validation of hypothesis that glial dysfunction and disrupted amino-acid neurotransmission contribute to the pathophysiology of depression and that modulation of glutamate metabolism, uptake and/or release represent viable targets for antidepressant drug development.

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Acknowledgements

We thank Dr Jane Taylor and Dr Angus Narin for the use of their locomotor activity apparatus and microwave fixation system. We also thank Richard Trinko and Xiaoxian Ma for their technical assistance with the acetate infusion studies, and Mathew Girgenti for his technical assistance with the in situ hybridization studies. This study was supported by NARSAD (2007 NARSAD Forster Bam Investigator GS), K02 (MH076222, GS), VA CT Research Enhancement Award Program (REAP) research center (GS and RSD), R01 (MH25642, RSD), R01 (MH45481, RSD), R01 (DK027121, KB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Drs James CK Lai, Fahmeed Hyder and Robin A de Graaf for helpful discussions and Dr Prajna P Siddiqui for performing the brain tissue extracts.

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Author notes

  1. M Banasr and G M I Chowdhury: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    M Banasr, R Terwilliger, S S Newton, R S Duman, K L Behar & G Sanacora

  2. Ribicoff Research Facilities, Yale University School of Medicine, New Haven, CT, USA

    M Banasr, R Terwilliger, S S Newton, R S Duman & G Sanacora

  3. Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, CT, USA

    G M I Chowdhury & K L Behar

  4. Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA

    G M I Chowdhury

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  1. M Banasr
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Corresponding author

Correspondence to G Sanacora.

Additional information

Author Contributions: Mounira Banasr was responsible for all animal treatments and behavioral analyses. She also contributed significantly to the study design and writing of the paper. Golam Chowdhury was responsible for conducting and analyzing the ex vivo 13C-NMR studies and contributed in the overall study design and preparation of the paper. Rose Twillinger and Dr Samuel Newton performed the in situ hybridization studies. Ronald S Duman contributed to design and analysis related to the behavioral and cellular components of the study, as well as the preparation of the paper. Kevin Behar contributed to design and analysis related to the NMR components of the study as well as the preparation of the paper. Gerard Sanacora provided the study's conception. He also coordinated all study activities and contributed significantly to the preparation of the paper.

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Banasr, M., Chowdhury, G., Terwilliger, R. et al. Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol Psychiatry 15, 501–511 (2010). https://doi.org/10.1038/mp.2008.106

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