Differential effects of chronic unpredictable stress on hippocampal CB1 receptors in male and female rats
Open accessAbstract
Chronic unpredictable mild stress (CMS), an animal model of depression, downregulates hippocampal CB1 receptors in adult male rats. Given that endocannabinoids are implicated in modulating stress and anxiety and that women are vulnerable to stress-related disorders, we tested the effects of CMS on both female and male rats. Gonadectomized (gndx) and gonadally intact male and female rats were exposed to a three-week chronic stress protocol. Following CMS, CB1 receptor and fatty-acid-amide-hydrolase (FAAH) expression levels in the hippocampus were assessed by western blot analysis. CMS reliably produced a downregulation of CB1 receptors ( approximately 50%) in the hippocampus of both gndx and intact males. This effect was more robust in the dorsal than in the ventral hippocampus. Conversely, CMS produced an upregulation of CB1 receptors ( approximately 150%) in the hippocampus of both gndx and intact females. This upregulation was only observed in the dorsal hippocampus of female animals. CMS produced an upregulation of FAAH levels in both male and female animals. In non-stress control animals, males were observed to have higher CB1 levels than females, but no differences in FAAH were found. These findings suggest that the endocannabinoid (eCB) system is preferentially organized in male and female animals to respond differentially to chronic stress. These sex differences in the eCB system may help development of novel treatments for stress and depression that are designed specifically for women and men.
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Animal studies have shown that chronic stress is associated with decreased brain levels of the endocannabinoid anandamide and CB1 receptor adaptations.
“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 [18]
Stress-related up-regulation of CB1 receptors is observed predominantly in female animals.
“with stress-related up-regulation of CB1 receptors observed predominantly in female animals18.”
From Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: A positron emission tomography study (2013) · cites this paper as [18]
In animals, CB1 receptor levels are higher in males than females.
“Animal data showing higher CB1 receptor levels in male relative to female animals18, 56, 57”
From Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: A positron emission tomography study (2013) · cites this paper as [18]
Rodents exposed to chronic stress show sustained enhancement of FAAH activity and prolonged reductions in tissue levels of BLA AEA that persist beyond exposure.
“Rodents exposed to chronic stress show sustained enhancement of FAAH activity and prolonged reductions in tissue levels of BLA AEA that persist beyond exposure [59,68,69].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [69]
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- Authors
- Reich, C. G., Taylor, M. E., & McCarthy, M. M.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Reich, Christian G.
- Venue
- Behavioural Brain Research
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 203
- Issue
- 2
- Pages
- 264-269
- ISSN
- 0166-4328 (ISSN-L)
- PMC
- PMC2747651
- OpenAlex
- W2033835916
- Cited by
- 244
- References
- 38
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 11 · 2023: 15 · 2022: 13 · 2021: 18 · 2020: 19 · 2019: 17 · 2018: 19 · 2017: 16 · 2016: 15 · 2015: 18 · 2014: 22 · 2013: 12 · 2012: 13
- FWCI
- 8.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Behavioural Brain Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (R03 MHO79294-01)
- National Institute of Neurological Disorders and Stroke (R01NS050525)
- 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
- chronic unpredictable mild stress, CB1 receptor, endocannabinoid system, hippocampus, sex differences, fatty acid amide hydrolase, depression, gonadectomy, stress response
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Animals, Corticosterone, Female, Hippocampus, Male, Sex Characteristics, Gonadal Steroid Hormones, Stress, Psychological, Blotting, Western, Down-Regulation, Up-Regulation, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1, Rats
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