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Cited by 349Cannabis and Cannabinoid ResearchStress Responses and CortisolNeuropeptides and Animal Physiology

Endogenous cannabinoid signaling is essential for stress adaptation

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Hill, Matthew N., McLaughlin, Ryan J., Bingham, Brenda, Shrestha, Lalita, Lee, Tiffany T. Y., Gray, J. Megan, Hillard, Cecilia J., Gorzalka, Boris B. +1 more·2010·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0914661107PMC PMC2889099
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Abstract

Secretion of glucocorticoid hormones during stress produces an array of physiological changes that are adaptive and beneficial in the short term. In the face of repeated stress exposure, however, habituation of the glucocorticoid response is essential as prolonged glucocorticoid secretion can produce deleterious effects on metabolic, immune, cardiovascular, and neurobiological function. Endocannabinoid signaling responds to and regulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis that governs the secretion of glucocorticoids; however, the role this system plays in adaptation of the neuroendocrine response to repeated stress is not well characterized. Herein, we demonstrate a divergent regulation of the two endocannabinoid ligands, N-arachidonylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), following repeated stress such that AEA content is persistently decreased throughout the corticolimbic stress circuit, whereas 2-AG is exclusively elevated within the amygdala in a stress-dependent manner. Pharmacological studies demonstrate that this divergent regulation of AEA and 2-AG contribute to distinct forms of HPA axis habituation. Inhibition of AEA hydrolysis prevented the development of basal hypersecretion of corticosterone following repeated stress. In contrast, systemic or intra-amygdalar administration of a CB(1) receptor antagonist before the final stress exposure prevented the repeated stress-induced decline in corticosterone responses. The present findings demonstrate an important role for endocannabinoid signaling in the process of stress HPA habituation, and suggest that AEA and 2-AG modulate different components of the adrenocortical response to repeated stressor exposure.

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Crossref · 10.1073/pnas.0914661107

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  • Recent studies in animals and humans point to a major role of EC signaling in both the periphery and central nervous system in controlling adaptive processes to aversive situations and regulating and limiting stress reactions.

    “Despite the abovementioned diversity in central and peripheral functions, recent studies in animals [9] and humans [10] point to a major role of EC signaling in both the periphery [10] and central nervous system [11] in controlling adaptive processes to aversive situations and regulating and limiting stress reactions.”

    From Plasma concentrations of endocannabinoids and related primary fatty acid amides in patients with post-traumatic stress disorder (2013) · cites this paper as [11]

  • Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior.

    “Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior.”

    From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [74]

  • Genetic loss or repeated, pre-stress pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and increases in HPA activity and anxiety-like behavior.

    “whereas genetic loss or repeated, pre-stress pharmacological inhibition (JNJ5003) of FAAH prevents stress-induced reductions in AEA and increases in HPA activity and anxiety-like behavior [68,73,74]”

    From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [74]

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Authors
Hill, M. N., McLaughlin, R. J., Bingham, B., Shrestha, L., Lee, T. T. Y., Gray, J. M., Hillard, C. J., Gorzalka, B. B., & Viau, V.
Affiliations
  • University of British Columbia (CA)
  • Rockefeller University (US)
  • Medical College of Wisconsin (US)
Corresponding author
Viau, Victor
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2010-05-03
Volume
107
Issue
20
Pages
9406-9411
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0914661107
PMC
PMC2889099
OpenAlex
W2048249572
Cited by
349
References
42
Citations by year
2026: 13 · 2025: 20 · 2024: 14 · 2023: 13 · 2022: 20 · 2021: 31 · 2020: 13 · 2019: 27 · 2018: 21 · 2017: 19 · 2016: 23 · 2015: 29 · 2014: 25 · 2013: 28 · 2012: 25
FWCI
18.87
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Michael Smith Health Research BC
  • National Institutes of Health
  • Canadian Institutes of Health Research
  • National Institute on Drug Abuse (R01DA009155, R21DA022439)
Topics
  • Health Sciences › Medicine › Pharmacology › 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
endocannabinoid signaling, repeated stress, anandamide, 2-arachidonoylglycerol, corticosterone, CB1 receptor, amygdala, stress adaptation
MeSH terms
Adaptation, Physiological, Analysis of Variance, Animals, Arachidonic Acids, Benzamides, Carbamates, Corticosterone, Male, Piperidines, Pyrazoles, Stress, Physiological, Signal Transduction, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1, Rats, Polyunsaturated Alkamides, Cannabinoid Receptor Modulators, Endocannabinoids

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