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Adaptations in endocannabinoid signaling in response to repeated homotypic stress: a novel mechanism for stress habituation
Open accessAbstract
Daily life stressors are a major environmental factor contributing to precipitation and exacerbation of mental illness. Animal models using repeated homotypic stress induce anxious and depressive phenotypes and are used to study the pathophysiology of affective disorders. Here we discuss data demonstrating that repeated homotypic stress produces temporally and anatomically distinct changes in endocannabinoid signaling components within stress‐responsive brain regions. We also present evidence describing the neural and behavioral correlates of these adaptations in endocannabinoid signaling. These data support a role for endocannabinoid signaling in the central nervous system response to chronic, homotypic stress, and specifically in the process of stress–response habituation. The clinical implications of these findings for the pathophysiology and treatment of affective disorders are discussed.
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“Recent preclinical evidence indicates that stress also mobilizes the endocannabinoid (eCB) system in both the brain and the periphery, and that the eCB system can modulate behavioral and endocrine responses to both acute and chronic stress (Hill et al, 2010;Patel and Hillard, 2008).”
From Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans (2012) · cites this paper as Patel and Hillard, 2008
In the citing paper
“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 [9]
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Citations
Cites
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
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Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor
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Hammen, C. (2005) · Annual Review of Clinical Psychology · doi:10.1146/annurev.clinpsy.1.102803.143938 · Cited by 2,979
Stress and Health: Psychological, Behavioral, and Biological Determinants
Schneiderman, N., Ironson, G., & Siegel, S. D. (2005) · Annual Review of Clinical Psychology · doi:10.1146/annurev.clinpsy.1.102803.144141 · Cited by 2,252
Cognitive vulnerability to emotional disorders
Mathews, A., & MacLeod, C. (2005) · Annual Review of Clinical Psychology · doi:10.1146/annurev.clinpsy.1.102803.143916 · Cited by 2,100
The molecular logic of endocannabinoid signalling
Piomelli, D. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1247 · Cited by 1,957
Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms
Pittenger, C., & Duman, R. S. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301574 · Cited by 1,795
The endogenous cannabinoid system controls extinction of aversive memories
Marsicano, G., Wotjak, C. T., Azad, S. C., Bisogno, T., Rammes, G., Cascio, M. G., Hermann, H., Tang, J., Hofmann, C., Zieglgänsberger, W., et al. (2002) · Nature · doi:10.1038/nature00839 · Cited by 1,728
Role of Endogenous Cannabinoids in Synaptic Signaling
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Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system
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Cited by
Sorted by citations
Neurobiological Interactions Between Stress and the Endocannabinoid System
Morena, M., Patel, S., Bains, J. S., & Hill, M. N. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.166 · Cited by 698
“…hypothetical model that eCB signaling is essential for stress adaptation and that the active recruitment of 2-AG signaling during repeated stress dampens neural circuits activated by stress, thereby resulting in a systems-level habituation to stress (Hill et al, 2010b; Patel and Hillard, 2008 ).”
BackgroundSelf-citationUncertainty and stress: Why it causes diseases and how it is mastered by the brain
Peters, A., McEwen, B. S., & Friston, K. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.05.004 · Cited by 652
“Stress habituation can be viewed as a special form of learning, in which not only the glucocorticoids, but also the endocannabinoids play a central role (Hill et al., 2010; Patel and Hillard, 2008).”
Endogenous cannabinoid signaling is essential for stress adaptation
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. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914661107 · Cited by 349
“A growing body of evidence suggests that endocannabinoid signaling also contributes to the process of stress habituation (8).”
BackgroundSelf-citationCampos, A. C., Ortega, Z., Palazuelos, J., Fogaça, M. V., Aguiar, D. C., Díaz-Alonso, J., Ortega-Gutiérrez, S., Vázquez-Villa, H., Moreira, F. A., Guzmán, M., et al. (2013) · International Journal of Neuropsychopharmacology · doi:10.1017/s1461145712001502 · Cited by 313
“An emerging paradigm from cannabinoid research is that the eCB system constitutes an allostatic signalling system that contributes to cellular plasticity responses in adaptation to stress-induced alterations (Patel and Hillard, 2008).”
BackgroundBest Practice & Research Clinical Endocrinology & Metabolism
Grieb, M. (2009) · Cited by 276
Metadata
- Authors
- Patel, S., & Hillard, C. J.
- Affiliations
- Vanderbilt University Medical Center (US)
- Medical College of Wisconsin (US)
- Corresponding author
- Patel, Sachin
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2008-06
- Volume
- 27
- Issue
- 11
- Pages
- 2821-2829
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- PMC
- PMC2593941
- OpenAlex
- W1981670902
- Cited by
- 162
- References
- 95
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 8 · 2021: 8 · 2020: 6 · 2019: 8 · 2018: 6 · 2017: 4 · 2016: 7 · 2015: 13 · 2014: 12 · 2013: 18 · 2012: 15
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (F30 DA15575, R01DA016967, F30DA015575, R21DA022439)
- 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 › Neurotransmitter Receptor Influence on Behavior
- Keywords
- endocannabinoid signaling, stress habituation, chronic stress, anxiety, depression, mood disorders
- MeSH terms
- Adaptation, Physiological, Animals, Anxiety Disorders, Brain, Depressive Disorder, Disease Models, Animal, Humans, Stress, Psychological, Mood Disorders, Cannabinoid Receptor Modulators, Endocannabinoids
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