Cited by 458Treatment of Major DepressionTryptophan and brain disordersStress Responses and Cortisol

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

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Banasr, M, Chowdhury, G M I, Terwilliger, R, Newton, S S, Duman, R S, Behar, K L, Sanacora, G·2010·Molecular Psychiatry

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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Crossref · 10.1038/mp.2008.106

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  • Riluzole increases glutamate-glutamine cycling, a potential explanation for in vitro observations of enhanced neuroplasticity and amelioration of excitotoxicity, as well as in vivo reductions in depressive behaviors.

    “Riluzole also increases glutamate–glutamine cycling, a potential explanation for in vitro observations of enhanced neuroplasticity and amelioration of excitotoxicity [176,177], as well as in vivo reductions in depressive behaviors [144,178].”

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  1. [1]Schildkaut JJ The catacholamine hypothesis of affective disorders: a review of supporting evidence Am J Psychiatry 1965 122 509 522 5319766

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Authors
Banasr, M., Chowdhury, G. M. I., Terwilliger, R., Newton, S. S., Duman, R. S., Behar, K. L., & Sanacora, G.
Affiliations
Yale University (US)
Corresponding author
Sanacora, G
Venue
Molecular Psychiatry
Published
2008-09-30
Volume
15
Issue
5
Pages
501-511
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
OpenAlex
W2004331086
Cited by
458
References
49
Citations by year
2026: 11 · 2025: 26 · 2024: 22 · 2023: 21 · 2022: 27 · 2021: 28 · 2020: 26 · 2019: 23 · 2018: 27 · 2017: 29 · 2016: 30 · 2015: 29 · 2014: 38 · 2013: 31 · 2012: 32
FWCI
13.60
Type
journal article
Language
en
Open access
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Alliance for Research on Schizophrenia and Depression
  • National Institutes of Health
  • National Institute of Mental Health (R01MH081211, K02MH076222, R37MH045481, P01MH025642, R01MH045481)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK027121)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
glial dysfunction, depression, chronic unpredictable mild stress, riluzole, prefrontal cortex, glutamate metabolism, glutamate uptake, glial fibrillary acidic protein, anhedonia, helplessness, antidepressant drug development, amino acid neurotransmission
MeSH terms
Acetates, Animals, Avoidance Learning, Behavioral Symptoms, Depression, Disease Models, Animal, Food Preferences, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Isotopes, Male, Neuroglia, Magnetic Resonance Spectroscopy, Radionuclide Imaging, RNA, Messenger, Stress, Psychological, Sucrose, Sweetening Agents, Rats, Sprague-Dawley, Prefrontal Cortex, Neuroprotective Agents, Glutamic Acid, Statistics, Nonparametric, Riluzole, Rats

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