Preservation of striatal cannabinoid CB1 receptor function correlates with the antianxiety effects of fatty acid amide hydrolase inhibition
Abstract
The endocannabinoid anandamide (AEA) plays a crucial role in emotional control, and inhibition of its degradation by the fatty acid amide hydrolase (FAAH) has a potent antianxiety effect. The mechanism by which the magnification of AEA activity reduces anxiety is still largely undetermined. By using FAAH mutant mice and both intraperitoneal and intracerebroventricular administration of the FAAH inhibitor (3'-(aminocarbonyl)[1,1'-biphenyl]-3-yl)-cyclohexylcarbamate (URB597), we found that enhanced AEA signaling reversed, via central cannabinoid CB1 receptors (CB1Rs), the anxious phenotype of mice exposed to social defeat stress. This behavioral effect was associated with preserved activity of CB1Rs regulating GABA transmission in the striatum, whereas these receptors were dramatically down-regulated by stress in control animals. The hypothalamic-pituitary-adrenal (HPA) axis was not involved in the antistress effects of FAAH inhibition, although the HPA axis is a biological target of endogenous AEA. We also provided some physiological indications that striatal CB1Rs regulating GABA synapses are not the receptor targets of FAAH inhibition, which rather resulted in the stimulation of striatal CB1Rs regulating glutamate transmission. Collectively, our findings suggest that preservation of cannabinoid CB1 receptor function within the striatum is a possible synaptic correlate of the antianxiety effects of FAAH inhibition.
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Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior.
“Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior.”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [73]
Genetic loss or repeated, pre-stress pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and increases in HPA activity and anxiety-like behavior.
“whereas genetic loss or repeated, pre-stress pharmacological inhibition (JNJ5003) of FAAH prevents stress-induced reductions in AEA and increases in HPA activity and anxiety-like behavior [68,73,74]”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [73]
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- Authors
- Rossi, S., De Chiara, V., Musella, A., Sacchetti, L., Cantarella, C., Castelli, M., Cavasinni, F., Motta, C., Studer, V., Bernardi, G., Cravatt, B. F., Maccarrone, M., Usiello, A., & Centonze, D.
- Affiliations
- University of Rome Tor Vergata (IT)
- Fondazione Santa Lucia (IT)
- Scripps Research Institute (US)
- University of Campania "Luigi Vanvitelli" (IT)
- ORCID
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2010-08
- Volume
- 78
- Issue
- 2
- Pages
- 260-268
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2067214410
- Cited by
- 82
- References
- 58
- Citations by year
- 2025: 4 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 6 · 2020: 6 · 2019: 3 · 2018: 5 · 2017: 8 · 2016: 6 · 2015: 10 · 2014: 5 · 2013: 6 · 2012: 9
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi dell Aquila (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- CB1 receptor, fatty acid amide hydrolase inhibition, anandamide, anxiolytic effects, social defeat stress, striatum, GABAergic synapses, glutamatergic synapses, hypothalamic-pituitary-adrenal axis, URB597, stress resilience
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Animals, Corpus Striatum, Enzyme Inhibitors, Anti-Anxiety Agents, Receptor, Cannabinoid, CB1, Mice
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