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Corticotropin-Releasing Hormone Drives Anandamide Hydrolysis in the Amygdala to Promote Anxiety
Open accessAbstract
Corticotropin-releasing hormone (CRH) is a central integrator in the brain of endocrine and behavioral stress responses, whereas activation of the endocannabinoid CB1 receptor suppresses these responses. Although these systems regulate overlapping functions, few studies have investigated whether these systems interact. Here we demonstrate a novel mechanism of CRH-induced anxiety that relies on modulation of endocannabinoids. Specifically, we found that CRH, through activation of the CRH receptor type 1 (CRHR1), evokes a rapid induction of the enzyme fatty acid amide hydrolase (FAAH), which causes a reduction in the endocannabinoid anandamide (AEA), within the amygdala. Similarly, the ability of acute stress to modulate amygdala FAAH and AEA in both rats and mice is also mediated through CRHR1 activation. This interaction occurs specifically in amygdala pyramidal neurons and represents a novel mechanism of endocannabinoid-CRH interactions in regulating amygdala output. Functionally, we found that CRH signaling in the amygdala promotes an anxious phenotype that is prevented by FAAH inhibition. Together, this work suggests that rapid reductions in amygdala AEA signaling following stress may prime the amygdala and facilitate the generation of downstream stress-linked behaviors. Given that endocannabinoid signaling is thought to exert "tonic" regulation on stress and anxiety responses, these data suggest that CRH signaling coordinates a disruption of tonic AEA activity to promote a state of anxiety, which in turn may represent an endogenous mechanism by which stress enhances anxiety. These data suggest that FAAH inhibitors may represent a novel class of anxiolytics that specifically target stress-induced anxiety.
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“under conditions of stress, FAAH activity has been found to be rapidly increased in brain regions regulating anxiety, such as the amygdala, with a concomitant reduction in the signaling pool of AEA (Bluett et al., 2014; Gray et al., 2015; Hill et al., 2013b; Patel et al., 2005; Rademacher et al., 2008).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Gray et al., 2015
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“gene deletion or selective pharmacological inhibition of FAAH, produced anxiolytic-like effects more reliably under conditions of high environmental aversiveness (Bluett et al., 2014; Carnevali et al., 2015; Gray et al., 2015; Haller et al., 2014; Haller et al., 2009; Hill et al., 2013b; Lomazzo et al., 2015; Naidu et al., 2007; Patel and Hillard, 2006; Rossi et al., 2010).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Gray et al., 2015
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Metadata
- Authors
- Gray, J. M., Vecchiarelli, H. A., Morena, M., Lee, T. T. Y., Hermanson, D. J., Kim, A. B., McLaughlin, R. J., Hassan, K. I., Kühne, C., Wotjak, C. T., Deussing, J. M., Patel, S., & Hill, M. N.
- Affiliations
- Hotchkiss Brain Institute (CA)
- University of Calgary (CA)
- University of British Columbia (CA)
- Washington State University (US)
- Max Planck Institute of Psychiatry (DE)
- Vanderbilt University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-03-04
- Volume
- 35
- Issue
- 9
- Pages
- 3879-3892
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4348185
- OpenAlex
- W2040268671
- Cited by
- 246
- References
- 82
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 17 · 2023: 16 · 2022: 21 · 2021: 32 · 2020: 22 · 2019: 22 · 2018: 22 · 2017: 23 · 2016: 17 · 2015: 21
- FWCI
- 19.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Pfizer
- Vanderbilt University
- Alberta Innovates
- Branch Out Neurological Foundation
- National Institutes of Health (MH090412)
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- National Institute of Mental Health (R21MH103515, R01MH100096, K08MH090412, MH090412)
- National Institute on Drug Abuse (DA031572, F31DA031572)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083211)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- corticotropin-releasing factor, anandamide, fatty acid amide hydrolase, amygdala, anxiety, CRHR1, endocannabinoid system, acute stress, FAAH inhibitors, anxiolytics, stress-induced anxiety
- MeSH terms
- CRF Receptor, Type 1, Fatty Acid Amide Hydrolases, Adrenocorticotropic Hormone, Amidohydrolases, Amygdala, Animals, Anxiety, Arachidonic Acids, Corticotropin-Releasing Hormone, Hydrolysis, Male, Stress, Psychological, Rats, Sprague-Dawley, Receptors, Corticotropin-Releasing Hormone, Mice, Knockout, Mice, Rats, Polyunsaturated Alkamides, Endocannabinoids
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