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2-Arachidonoylglycerol Modulation of Anxiety and Stress Adaptation: From Grass Roots to Novel Therapeutics

  • Gaurav Bedse
    Affiliations
    Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee

    Department of Vanderbilt Center for Addiction Research, Vanderbilt University Medical Center, Nashville, Tennessee
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  • Mathew N. Hill
    Affiliations
    Department of Cell Biology, Hotchkiss Brain Institute and Mathison Center for Mental Health Research and Education, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Department of Anatomy and Psychiatry, Hotchkiss Brain Institute and Mathison Center for Mental Health Research and Education, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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  • Sachin Patel
    Correspondence
    Address correspondence to Sachin Patel, M.D., Ph.D., Vanderbilt University Medical Center, Medical Research Building IV, Room 8425B, 2213 Garland Avenue, Nashville, TN 37232.
    Affiliations
    Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee

    Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee

    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee

    Department of Vanderbilt Center for Addiction Research, Vanderbilt University Medical Center, Nashville, Tennessee
    Search for articles by this author

      Abstract

      Over the past decade there has been a surge of interest in the development of endocannabinoid-based therapeutic approaches for the treatment of diverse neuropsychiatric conditions. Although initial preclinical and clinical development efforts focused on pharmacological inhibition of fatty acid amide hydrolase to elevate levels of the endocannabinoid anandamide, more recent efforts have focused on inhibition of monoacylglycerol lipase (MAGL) to enhance signaling of the most abundant and efficacious endocannabinoid ligand, 2-arachidonoylglycerol (2-AG). We review the biochemistry and physiology of 2-AG signaling and preclinical evidence supporting a role for this system in the regulation of anxiety-related outcomes and stress adaptation. We review preclinical evidence supporting MAGL inhibition for the treatment of affective, trauma-related, and stress-related disorders; describe the current state of MAGL inhibitor drug development; and discuss biological factors that could affect MAGL inhibitor efficacy. Issues related to the clinical advancement of MAGL inhibitors are also discussed. We are cautiously optimistic, as the field of MAGL inhibitor development transitions from preclinical to clinical and theoretical to practical, that pharmacological 2-AG augmentation could represent a mechanistically novel therapeutic approach for the treatment of affective and stress-related neuropsychiatric disorders.

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