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Downregulation of Endocannabinoid Signaling in the Hippocampus Following Chronic Unpredictable Stress
Abstract
Deficits in cognitive functioning and flexibility are seen following both chronic stress and modulation of endogenous cannabinoid (eCB) signaling. Here, we investigated whether alterations in eCB signaling might contribute to the cognitive impairments induced by chronic stress. Chronic stress impaired reversal learning and induced perseveratory behavior in the Morris water maze without significant effect on task acquisition. These cognitive impairments were reversed by exogenous cannabinoid administration, suggesting deficient eCB signaling underlies these phenomena. In line with this hypothesis, chronic stress downregulated CB1 receptor expression and significantly reduced the content of the endocannabinoid 2-arachidonylglycerol within the hippocampus. CB1 receptor density and 2-arachidonylglycerol content were unaffected in the limbic forebrain. These data suggest that stress-induced downregulation of hippocampal eCB signaling contributes to problems in behavioral flexibility and could play a role in the development of perseveratory and ruminatory behaviors in stress-related neuropsychiatric disorders.
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“Animal studies17 have shown that chronic stress is associated with decreased brain levels of the endocannabinoid anandamide and CB1 receptor adaptations17–19”
From Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: A positron emission tomography study (2013) · cites this paper as [17]
In the citing paper
“chronic unpredictable stressors have been shown to impair 2-AG signaling (Hill et al., 2005; Zhang et al., 2015)”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Hill et al., 2005
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Metadata
- Authors
- Hill, M. N., Patel, S., Carrier, E. J., Rademacher, D. J., Ormerod, B. K., Hillard, C. J., & Gorzalka, B. B.
- Affiliations
- University of British Columbia (CA)
- Medical College of Wisconsin (US)
- Corresponding author
- Hillard, Cecilia J
- Gorzalka, Boris B
- Venue
- Neuropsychopharmacology
- Published
- 2004-11-03
- Volume
- 30
- Issue
- 3
- Pages
- 508-515
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- OpenAlex
- W2124037107
- Cited by
- 363
- References
- 56
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 16 · 2023: 7 · 2022: 12 · 2021: 29 · 2020: 15 · 2019: 15 · 2018: 11 · 2017: 14 · 2016: 20 · 2015: 21 · 2014: 21 · 2013: 18 · 2012: 20
- FWCI
- 8.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- Michael Smith Health Research BC
- National Institutes of Health
- Natural Sciences and Engineering Research Council of Canada
- National Institute on Drug Abuse (F32 DA-16510, F30 DA15575, R01DA016967, F30DA015575, F32DA016510)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- endocannabinoid signaling, chronic unpredictable mild stress, hippocampus, CB1 receptor, 2-arachidonoylglycerol, reversal learning, behavioral flexibility, perseveration, cognitive impairment, stress-related neuropsychiatric disorders
- MeSH terms
- Animals, Cannabinoids, Copulation, Female, Hippocampus, Male, Reference Values, Stress, Psychological, Signal Transduction, Maze Learning, Rats, Long-Evans, Receptor, Cannabinoid, CB1, Rats, Cannabinoid Receptor Modulators, Endocannabinoids
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