Cited by 363Cannabis and Cannabinoid ResearchStress Responses and CortisolMemory and Neural Mechanisms

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Downregulation of Endocannabinoid Signaling in the Hippocampus Following Chronic Unpredictable Stress

Hill, Matthew N, Patel, Sachin, Carrier, Erica J, Rademacher, David J, Ormerod, Brandi K, Hillard, Cecilia J, Gorzalka, Boris B·2005·Neuropsychopharmacology

DOI 10.1038/sj.npp.1300601

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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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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
ORCID: Hill, Matthew N
Patel, Sachin
Carrier, Erica J
Ormerod, Brandi K
Hillard, Cecilia J
Venue: Neuropsychopharmacology
Publisher: Springer Science and Business Media LLC
Published: 2004-11-03
Volume: 30
Issue: 3
Pages: 508-515
ISSN: 0893-133X (ISSN-L)
1740-634X
DOI: 10.1038/sj.npp.1300601
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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Downregulation of Endocannabinoid Signaling in the Hippocampus Following Chronic Unpredictable Stress

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