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Metabotropic Glutamatergic Receptor 5 and Stress Disorders: Knowledge Gained From Receptor Imaging Studies

  • Irina Esterlis
    Correspondence
    Address correspondence to Irina Esterlis, Ph.D., Yale Translational Brain Imaging Program, 2 Church Street South, Suite 511, New Haven, CT 06514.
    Affiliations
    Department of Psychiatry, Yale University, New Haven, Connecticut

    US Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, Veteran’s Affairs Connecticut Healthcare System, West Haven, Connecticut
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  • Sophie E. Holmes
    Affiliations
    Department of Psychiatry, Yale University, New Haven, Connecticut
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  • Priya Sharma
    Affiliations
    Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada

    London Health Sciences Centre, Victoria Hospital, London, Ontario, Canada
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  • John H. Krystal
    Affiliations
    Department of Psychiatry, Yale University, New Haven, Connecticut

    Department of Neuroscience, Yale University, New Haven, Connecticut

    US Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, Veteran’s Affairs Connecticut Healthcare System, West Haven, Connecticut
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  • Christine DeLorenzo
    Affiliations
    Department of Psychiatry, Stony Brook University, Stony Brook, New York

    Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York
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Published:September 18, 2017DOI:https://doi.org/10.1016/j.biopsych.2017.08.025

      Abstract

      The metabotropic glutamatergic receptor subtype 5 (mGluR5) may represent a promising therapeutic target for stress-related psychiatric disorders. Here, we describe mGluR5 findings in stress disorders, particularly major depressive disorder (MDD), highlighting insights from positron emission tomography studies. Positron emission tomography studies report either no differences or lower mGluR5 in MDD, potentially reflecting MDD heterogeneity. Unlike the rapidly acting glutamatergic agent ketamine, mGluR5-specific modulation has not yet shown antidepressant efficacy in MDD and bipolar disorder. Although we recently showed that ketamine may work, in part, through significant mGluR5 modulation, the specific role of mGluR5 downregulation in ketamine’s antidepressant response is unclear. In contrast to MDD, there has been much less investigation of mGluR5 in bipolar disorder, yet initial studies indicate that mGluR5-specific treatments may aid in both depressed and manic mood states. The direction of modulation needed may be state dependent, however, limiting clinical feasibility. There has been relatively little study of posttraumatic stress disorder or obsessive-compulsive disorder to date, although there is evidence for the upregulation of mGluR5 in these disorders. However, while antagonism of mGluR5 may reduce fear conditioning, it may also reduce fear extinction. Therefore, studies are needed to determine the role mGluR5 modulation might play in the treatment of these conditions. Further challenges in modulating this prevalent neurotransmitter system include potential induction of significant side effects. As such, more research is needed to identify level and type (positive/negative allosteric modulation or full antagonism) of mGluR5 modulation required to translate existing knowledge into improved therapies.

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