Antidepressant-like activity and cardioprotective effects of fatty acid amide hydrolase inhibitor URB694 in socially stressed Wistar Kyoto rats
Open accessAbstract
In humans, depression is often triggered by prolonged exposure to psychosocial stressors and is often associated with cardiovascular comorbidity. Mounting evidence suggests a role for endocannabinoid signaling in the regulation of both emotional behavior and cardiovascular function. Here, we examined cardiac activity in a rodent model of social stress-induced depression and investigated whether pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid anandamide, exerts antidepressant-like and cardioprotective effects. Male Wistar Kyoto rats were exposed to five weeks of repeated social stress or control procedure. Starting from the third week, they received daily administration of the selective FAAH inhibitor URB694 (0.1 mg/kg, i.p.) or vehicle. Cardiac electrical activity was recorded by radiotelemetry. Repeated social stress triggered biological and behavioral changes that mirror symptoms of human depression, such as (i) reductions in body weight gain and sucrose solution preference, (ii) hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and (iii) increased immobility in the forced swim test. Moreover, stressed rats showed (i) alterations in heart rate daily rhythm and cardiac autonomic neural regulation, (ii) a larger incidence of spontaneous arrhythmias, and (iii) signs of cardiac hypertrophy. Daily treatment with URB694 (i) increased central and peripheral anandamide levels, (ii) corrected stress-induced alterations of biological and behavioral parameters, and (iii) protected the heart against the adverse effects of social stress. Repeated social stress in Wistar Kyoto rats reproduces aspects of human depression/cardiovascular comorbidity. Pharmacological enhancement of anandamide signaling might be a promising strategy for the treatment of these comorbid conditions.
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Gene deletion or selective pharmacological inhibition of FAAH produces anxiolytic-like effects more reliably under conditions of high environmental aversiveness.
“gene deletion or selective pharmacological inhibition of FAAH, produced anxiolytic-like effects more reliably under conditions of high environmental aversiveness (Bluett et al., 2014; Carnevali et al., 2015; Gray et al., 2015; Haller et al., 2014; Haller et al., 2009; Hill et al., 2013b; Lomazzo et al., 2015; Naidu et al., 2007; Patel and Hillard, 2006; Rossi et al., 2010).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Carnevali et al., 2015
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Imaging the endocannabinoid enzyme fatty acid amide hydrolase in the living human brain
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- Authors
- Carnevali, L., Vacondio, F., Rossi, S., Callegari, S., Macchi, E., Spadoni, G., Bedini, A., Rivara, S., Mor, M., & Sgoifo, A.
- Affiliations
- University of Parma (IT)
- University of Urbino (IT)
- Corresponding author
- Sgoifo, Andrea
- ORCID
- Venue
- European Neuropsychopharmacology
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 25
- Issue
- 11
- Pages
- 2157-2169
- ISSN
- 0924-977X (ISSN-L)
- OpenAlex
- W1002042317
- Cited by
- 34
- References
- 65
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 5 · 2019: 4 · 2018: 2 · 2017: 7 · 2016: 3 · 2015: 1
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- cc-by-nc-nd
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- Locations
- European Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion, cc-by-nc-nd)
- Funders
- University of Parma (FIL 2012)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- fatty acid amide hydrolase inhibition, anandamide, endocannabinoid system, social stress, depression, cardiovascular comorbidity, cardioprotection, cardiac arrhythmias, cardiac hypertrophy, heart rate variability, hypothalamic-pituitary-adrenal axis, antidepressant-like effects, Wistar-Kyoto rats
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Animals, Antidepressive Agents, Arrhythmias, Cardiac, Biphenyl Compounds, Body Weight, Carbamates, Cardiotonic Agents, Choice Behavior, Corticosterone, Depressive Disorder, Disease Models, Animal, Food Preferences, Heart Rate, Male, Rats, Inbred WKY, Stress, Psychological, Dietary Sucrose, Anhedonia
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