Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and medial prefrontal cortex in mice
Abstract
Endocannabinoid signaling has been implicated in habituation to repeated stress. The hypothesis that repeated exposures to stress alters endocannabinoid signaling in the limbic circuit was tested by restraining male mice for 30 min/day for 1, 7, or 10 days and measuring brain endocannabinoid content. Amygdalar N-arachidonylethanolamine was decreased after 1, 7, and 10 restraint episodes; 2-arachidonylglycerol was increased after the 10th restraint. A similar pattern occurred in the medial prefrontal cortex (mPFC): N-arachidonylethanolamine was decreased after the 7th and 10th restraints and 2-arachidonylglycerol was increased after the 10th restraint. In the ventral striatum, the pattern reversed: N-arachidonylethanolamine was increased after the 10th restraint and 2-arachidonylglycerol was decreased after the 7th restraint. Palmitoylethanolamide contents changed in parallel with N-arachidonylethanolamine in the amygdala and ventral striatum. A single restraint episode did not affect the activity of fatty acid amide hydrolase (FAAH) in any of the brain regions examined. After the 10th restraint, both V(max) and K(m) for N-arachidonylethanolamine were increased in the mPFC; while only the V(max) was increased in the amygdala. On the other hand, the V(max) of FAAH was decreased in ventral striatum after the 10th restraint. After the 10th restraint, the maximum velocity for 2-oleoylglycerol hydrolysis was increased in mPFC; no other changes in 2-oleoylglycerol hydrolysis occurred. Repeated exposure to restraint produced no changes in CB(1) receptor density in any of the areas examined. These studies are consistent with the hypothesis that stress exposure alters endocannabinoid signaling in the brain and that alterations in endocannabinoid signaling occur during habituation to stress.
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Peripheral glucocorticoid concentrations after stress are correlated with reduced AEA concentrations in stress-responsive regions of the brain.
“Preclinical studies indicate that peripheral glucocorticoid concentrations after stress are correlated with reduced AEA concentrations in stress-responsive regions of the brain (Patel et al, 2004(Patel et al, , 2005a;;Rademacher et al, 2008;Hill et al, 2009b).”
From Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans (2012) · cites this paper as Rademacher et al, 2008
Stress produces divergent effects on AEA and 2-AG levels in the BLA, with an elevation in 2-AG levels and a rapid induction of FAAH activity and resultant decline in the AEA pool following exposure to various types of stress.
“Interestingly, stress appears to produce divergent effects on AEA and 2-AG levels in the BLA – with an elevation in 2-AG levels [57], but a rapid induction of FAAH activity and a resultant decline in the pool of AEA [58–60] were reported following exposure to various types of stress.”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [59]
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 [59]
AEA content in the BLA is reduced at the termination of restraint stress and is negatively correlated with the magnitude of the CORT response to stress.
“Hill et al (2009) have recently shown that the content of AEA in the BLA is reduced at the termination of restraint stress (also see Patel et al, 2005a andRademacher et al, 2008) and that AEA content is negatively correlated with the magnitude of the CORT response to stress.”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Rademacher et al, 2008
Exposure to stress causes significant reductions in amygdalar and hippocampal AEA content.
“On the other hand, exposure to stress causes significant reductions in amygdalar and hippocampal AEA content (Patel et al, 2005a;Hill et al, 2005;Rademacher et al, 2008;Gorzalka et al, 2008).”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Rademacher et al, 2008
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References 42 · Cited by 233
- Authors
- Rademacher, D. J., Meier, S. E., Shi, L., Vanessa Ho, W.-S., Jarrahian, A., & Hillard, C. J.
- Affiliations
- Medical College of Wisconsin (US)
- Butler University (US)
- Corresponding author
- Hillard, Cecilia J.
- ORCID
- Hillard, Cecilia J.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2008-01
- Volume
- 54
- Issue
- 1
- Pages
- 108-116
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2028623309
- Cited by
- 233
- References
- 42
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 8 · 2023: 8 · 2022: 9 · 2021: 14 · 2020: 10 · 2019: 8 · 2018: 15 · 2017: 15 · 2016: 21 · 2015: 21 · 2014: 12 · 2013: 15 · 2012: 14
- FWCI
- 6.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (F32 DA-16510, R01 DA16967, R01DA016967, F32DA016510)
- 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 › Neuroscience and Neuropharmacology Research
- Keywords
- endocannabinoid system, restraint stress, repeated stress, 2-arachidonoylglycerol, palmitoylethanolamide, fatty acid amide hydrolase, amygdala, ventral striatum, medial prefrontal cortex, limbic circuits, mice
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Amygdala, Analysis of Variance, Animals, Corpus Striatum, Corticosterone, Cyclohexanols, Enzyme-Linked Immunosorbent Assay, Glycerides, Male, Mice, Inbred ICR, Protein Binding, Restraint, Physical, Stress, Psychological, Time Factors, Tritium, Prefrontal Cortex, Mice, Cannabinoid Receptor Modulators, Endocannabinoids
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