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Cannabinoids Elicit Antidepressant-Like Behavior and Activate Serotonergic Neurons through the Medial Prefrontal Cortex
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Preclinical and clinical studies show that cannabis modulates mood and possesses antidepressant-like properties, mediated by the agonistic activity of cannabinoids on central CB 1 receptors (CB 1 Rs). The action of CB 1 R agonists on the serotonin (5-HT) system, the major transmitter system involved in mood control and implicated in the mechanism of action of antidepressants, remains however poorly understood. In this study, we demonstrated that, at low doses, the CB 1 R agonist WIN55,212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate] exerts potent antidepressant-like properties in the rat forced-swim test (FST). This effect is CB 1 R dependent because it was blocked by the CB 1 R antagonist rimonabant and is 5-HT mediated because it was abolished by pretreatment with the 5-HT-depleting agent parachlorophenylalanine. Then, using in vivo electrophysiology, we showed that low doses of WIN55,212-2 dose dependently enhanced dorsal raphe nucleus 5-HT neuronal activity through a CB 1 R-dependent mechanism. Conversely, high doses of WIN55,212-2 were ineffective in the FST and decreased 5-HT neuronal activity through a CB 1 R-independent mechanism. The CB 1 R agonist-induced enhancement of 5-HT neuronal activity was abolished by total or medial prefrontocortical, but not by lateral prefrontocortical, transection. Furthermore, 5-HT neuronal activity was enhanced by the local microinjection of WIN55,212-2 into the ventromedial prefrontal cortex (mPFCv) but not by the local microinjection of WIN55,212-2 into the lateral prefrontal cortex. Similarly, the microinjection of WIN55,212-2 into the mPFCv produced a CB 1 R-dependent antidepressant-like effect in the FST. These results demonstrate that CB 1 R agonists possess antidepressant-like properties and modulate 5-HT neuronal activity via the mPFCv.
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“This is in agreement with a clinical study (Hill et al, 2008) as well as with findings in nonhuman models, in which inhibition of AEA metabolism has anxiolytic and antidepressant effects (Bambico et al, 2007;Naidu et al, 2007).”
From Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans (2012) · cites this paper as Bambico et al, 2007
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Metadata
- Authors
- Bambico, F. R., Katz, N., Debonnel, G., & Gobbi, G.
- Affiliations
- McGill University (CA)
- Institut universitaire en santé mentale de Montréal (CA)
- Corresponding author
- Gobbi, Gabriella
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-10-24
- Volume
- 27
- Issue
- 43
- Pages
- 11700-11711
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6673235
- OpenAlex
- W2073174105
- Cited by
- 325
- References
- 81
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 14 · 2023: 12 · 2022: 15 · 2021: 27 · 2020: 20 · 2019: 19 · 2018: 20 · 2017: 14 · 2016: 13 · 2015: 13 · 2014: 15 · 2013: 14 · 2012: 27
- FWCI
- 13.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- McGill University
- McGill University Health Centre
- Canadian Psychiatric Research Foundation
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- cannabinoids, CB1 receptor agonists, WIN 55,212-2, antidepressant-like behavior, serotonin, dorsal raphe nucleus, ventromedial prefrontal cortex, forced swim test, rimonabant, p-chlorophenylalanine, depression
- MeSH terms
- Animals, Antidepressive Agents, Cannabinoids, Depression, Male, Morpholines, Naphthalenes, Neurons, Serotonin, Rats, Sprague-Dawley, Prefrontal Cortex, Receptor, Cannabinoid, CB1, Benzoxazines, Rats
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