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The Endocannabinoid 2-Arachidonoylglycerol Bidirectionally Modulates Acute and Protracted Effects of Predator Odor Exposure

  • Author Footnotes
    1 VK and AM contributed equally to this work.
    Veronika Kondev
    Footnotes
    1 VK and AM contributed equally to this work.
    Affiliations
    Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee
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  • Author Footnotes
    1 VK and AM contributed equally to this work.
    Amanda Morgan
    Footnotes
    1 VK and AM contributed equally to this work.
    Affiliations
    Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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  • Mustafa Najeed
    Affiliations
    Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee
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  • Nathan D. Winters
    Affiliations
    Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee
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  • Philip J. Kingsley
    Affiliations
    Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee

    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee

    Department of Chemistry, Vanderbilt University School of Medicine, Nashville, Tennessee
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  • Lawrence Marnett
    Affiliations
    Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee

    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee

    Department of Chemistry, Vanderbilt University School of Medicine, Nashville, Tennessee
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  • Sachin Patel
    Correspondence
    Address correspondence to Sachin Patel, M.D., Ph.D.
    Affiliations
    Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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  • Author Footnotes
    1 VK and AM contributed equally to this work.

      Abstract

      Background

      Stress-related disorders are among the most prevalent psychiatric disorders, characterized by excess fear and enhanced avoidance of trauma triggers. Elucidating the mechanisms regulating temporally distinct aspects of innate and conditioned fear responses could facilitate novel therapeutic development for stress-related disorders. One potential target that has recently emerged is the endocannabinoid system, which has been reported to mediate the physiological response to stress and represents an important substrate underlying individual differences in stress susceptibility.

      Methods

      Here, we exposed male and female CD-1 mice to an innate predator stressor, 2MT (2-methyl-2-thiazoline), to investigate the ability of endocannabinoid signaling to modulate temporally distinct innate and conditioned fear behaviors.

      Results

      We found that 2MT exposure increased amygdala 2-AG (2-arachidonoylglycerol) content and selectively increased excitability in central, but not basolateral, amygdala neurons. We also found that pharmacological 2-AG augmentation during stress exposure exacerbated both acute freezing responses and central amygdala hyperexcitability via cannabinoid receptor type 1– and type 2–dependent mechanisms. Finally, 2-AG augmentation during stress exposure reduced long-term contextual conditioned freezing, and 2-AG augmentation 24 hours after stress exposure reduced conditioned avoidance behavior.

      Conclusions

      Our findings demonstrate a bidirectional effect of 2-AG augmentation on innate and conditioned fear behavior, with enhancement of 2-AG levels during stress promoting innate fear responses but ultimately resulting in long-term conditioned fear reduction. These data could reconcile contradictory data on the role of 2-AG in the regulation of innate and conditioned fear-related behavioral responses.

      Keywords

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