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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
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“Preclinical and clinical studies have shed light into the role endocannabinoids play both in stress-coping processes and in the susceptibility to develop trauma-related psychopathologies (Hill et al. 2010b; Kathuria et al. 2003; Mayo et al. 2022; Patel and Hillard 2008; Stopponi et al. 2018).”
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Self-citationHypothalamic endocannabinoid signalling modulates aversive responses related to panic attacks
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Swim stress differentially affects limbic contents of 2-arachidonoylglycerol and 2-oleoylglycerol
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“While a single episode of 30 minute restraint does not reliably alter 2- AG contents in brain, repeated exposure of mice to the same restraint stress increases 2-AG contents in limbic brain regions after 5–10 repetitions (Patel et al., 2005, Rademacher et al., 2008).”
Self-citationZamberletti, E., & Rubino, T. (2020) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2020.06.013 · Cited by 17
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“Finally, considering theoretical and known eCB system involvements in recovery from acute stress (Riebe and Wotjak, 2011), and modulation of reactivity to repeatedly experienced stressors, which may involve stimulation or stress-dependent alterations in CB1R activity (Hill et al., 2010a; Newsom et al., 2019; Patel and…”
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“Therefore, habituation to stress manifests itself as a specific form of synaptic and morphological plasticity, in the induction of which not only glucocorticoids but also endocannabinoids play a key role (Patel and Hillard, 2008; Hill et al., 2010a).”
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“5 2-AG signaling has been shown to play a prominent role in modulating stress effects after repeated homotypic stress exposures (Bluett et al., 2017; Patel and Hillard, 2008; Rademacher et al., 2008).”
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“Since stress and anxiety disorders (Kamprath et al., 2009; Patel and Hillard, 2008), as well as depression (Hungund et al.”
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“On the other hand, studies have reported habituation of several of these responses after the repeated stimulation of stress-responsive brain regions through homotypic stressful stimuli (Capriles and Cancela, 1999; Moghaddam, 2002; Patel and Hillard, 2008).”
BackgroundCannabinoid Modulation of Midbrain Urocortin 1 Neurones During Acute and Chronic Stress
Derks, N. M., Pintér, O., Zuure, W. A., Ledent, C. A., Watanabe, M., Molnár, C. S., Wei, Y., Roubos, E. W., Wu, S., Hrabovszky, E., et al. (2012) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2012.02355.x · Cited by 8
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“Repeated stress has been reported to result in stress-induced elevations of eCB ligands in stress-reactive limbic structures in patterns different than those reported to occur after acute stress (Hill et al., 2010; Patel et al., 2004, 2005; Patel and Hillard, 2008).”
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“In particular, the role of endocannabinoids in response to stress was identified [127], with preclinical evidence showing that AEA and 2-AG play critical roles in the regulation of the glucocorticoid response to stress [128–132].”
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“The endocannabinoid system is also linked to stress release, and CB1 receptors in the prefrontal cortex may influence anxiety, chronic stress, motivation, and social functioning in general [45].”
BackgroundCannabis, endocannabinoids and neurodevelopment
Galve‐Roperh, I. (2011) · Cambridge University Press eBooks · doi:10.1017/cbo9780511706080.007 · Cited by 6
Lightfoot, S. H. M., Baglot, S. L., Hume, C., Grace, L. M., McLaughlin, R. J., & Hill, M. N. (2024) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2024.107263 · Cited by 4
“…of CB1 receptors can modulate the HPA axis, although the direction of these effects is strongly influenced by whether activation occurs through endogenous or exogenous ligands (Glodosky et al., 2021; Hill and McEwen, 2010; Morena et al., 2016; Patel et al., 2004; Patel and Hillard, 2008).”
Stress and Behavior: The Role of Nutrients with Emphasis on Omega-3 Fatty Acids
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“Previous studies have implicated 2-AG signaling in stress adaptation and modulation of anxiety-like behavior after stress exposure (Bedse et al. 2017; Bluett et al. 2017; Marcus et al. 2020; Patel et al. 2005; Patel and Hillard 2008; Patel et al. 2009).”
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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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