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Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure

Molecular Psychiatry volume 18, pages 1125–1135 (2013)Cite this article

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Abstract

Hyperactivation of the amygdala following chronic stress is believed to be one of the primary mechanisms underlying the increased propensity for anxiety-like behaviors and pathological states; however, the mechanisms by which chronic stress modulates amygdalar function are not well characterized. The aim of the current study was to determine the extent to which the endocannabinoid (eCB) system, which is known to regulate emotional behavior and neuroplasticity, contributes to changes in amygdalar structure and function following chronic stress. To examine the hypothesis, we have exposed C57/Bl6 mice to chronic restraint stress, which results in an increase in fatty acid amide hydrolase (FAAH) activity and a reduction in the concentration of the eCB N-arachidonylethanolamine (AEA) within the amygdala. Chronic restraint stress also increased dendritic arborization, complexity and spine density of pyramidal neurons in the basolateral nucleus of the amygdala (BLA) and increased anxiety-like behavior in wild-type mice. All of the stress-induced changes in amygdalar structure and function were absent in mice deficient in FAAH. Further, the anti-anxiety effect of FAAH deletion was recapitulated in rats treated orally with a novel pharmacological inhibitor of FAAH, JNJ5003 (50 mg per kg per day), during exposure to chronic stress. These studies suggest that FAAH is required for chronic stress to induce hyperactivity and structural remodeling of the amygdala. Collectively, these studies indicate that FAAH-mediated decreases in AEA occur following chronic stress and that this loss of AEA signaling is functionally relevant to the effects of chronic stress. These data support the hypothesis that inhibition of FAAH has therapeutic potential in the treatment of anxiety disorders, possibly by maintaining normal amygdalar function in the face of chronic stress.

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Acknowledgements

We thank Katharine McCarthy, Ilia Karatsoreos and Melinda Miller for their technical assistance on the execution of these studies. This research was supported by operating grants from the National Institutes of Health grants MH41256 (BSM), DA09155 and DA026996 (CJH) and the Lightfighter Trust (BSM), as well as an unrestricted research grant from Johnson and Johnson (BSM). SC and SAK are supported by funds from the National Centre for Biological Sciences (NCBS). MNH was the recipient of a postdoctoral fellowship from the Canadian Institutes of Health Research.

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Authors and Affiliations

  1. Department of Cell Biology and Anatomy & Psychiatry, The Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada

    M N Hill

  2. Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA

    M N Hill, S B Filipski & B S McEwen

  3. National Centre for Biological Sciences, Bangalore, India

    S A Kumar & S Chattarji

  4. Neuroscience Research Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA

    M Iverson, K L Stuhr & C J Hillard

  5. Janssen Research and Development, L.L.C., San Diego, CA, USA

    J M Keith

  6. The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA

    B F Cravatt

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This research was supported, in part, by an unrestricted operating grant to BSM from Johnson and Johnson Pharmaceuticals. JMK is an employee of Janssen Research and Development LLC, of Johnson and Johnson Pharmaceuticals. The funding body had no role in the design of this study, collection or analysis of the data or decision to publish, outside of the development of the pharmacological compound, JNJ-5003, which was developed and used in a portion of this study.

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Hill, M., Kumar, S., Filipski, S. et al. Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure. Mol Psychiatry 18, 1125–1135 (2013). https://doi.org/10.1038/mp.2012.90

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