Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay
Open accessAbstract
Cannabinoids have long been shown to have a range of potential therapeutic effects, including antiemetic actions, analgesia, and anxiolysis. However, psychomimetic and memory disruptive side effects, as well as the potential for abuse and dependence, have restricted their clinical development. Endogenous cannabinoids (i.e., endocannabinoids; eCBs), such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are produced throughout the limbic system and other brain regions associated with emotionality and are believed to modulate behavioral responses to stress-related conditions. AEA and 2-AG are rapidly metabolized by the respective enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Accordingly, inhibition of each enzyme increases brain levels of the appropriate eCB. Although FAAH inhibition has been established to decrease anxiety-like behavior, the role of 2-AG has been difficult to ascertain until the recent synthesis of JZL184, a potent and selective MAGL inhibitor. In the present study, we investigated the effects of inhibiting FAAH or MAGL on anxiety-like behavior in marble burying, a model of repetitive, compulsive behaviors germane to anxiety disorders such as obsessive-compulsive disorder. The FAAH inhibitor PF-3845, the MAGL inhibitor JZL184, and the benzodiazepine diazepam decreased marble burying at doses that did not affect locomotor activity. In contrast, Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana, did not consistently reduce marble burying without also eliciting profound decreases in locomotor behavior. The CB1 cannabinoid receptor antagonist rimonabant blocked the reduction in marble burying caused by FAAH and MAGL inhibitors, but not by diazepam, indicating a CB1 receptor mechanism of action. These data indicate that elevation of AEA or 2-AG reduces marble burying behavior and suggest that their catabolic enzymes represent potential targets for the development of new classes of pharmacotherapeutics to treat anxiety-related disorders.
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Systemically administered MAGL inhibitors acutely reduce anxiety-like behavior.
“In this context, systemically administered MAGL inhibitors have been shown to acutely reduce anxiety-like behavior [75–78]”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [76]
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- Authors
- Kinsey, S. G., O'Neal, S. T., Long, J. Z., Cravatt, B. F., & Lichtman, A. H.
- Affiliations
- Virginia Commonwealth University (US)
- Scripps Research Institute (US)
- Corresponding author
- Kinsey, Steven G.
- Venue
- Pharmacology Biochemistry and Behavior
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 98
- Issue
- 1
- Pages
- 21-27
- ISSN
- 0091-3057 (ISSN-L)
- PMC
- PMC3034086
- OpenAlex
- W1965536242
- Cited by
- 170
- References
- 41
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 1 · 2023: 1 · 2022: 8 · 2021: 12 · 2020: 15 · 2019: 5 · 2018: 13 · 2017: 12 · 2016: 9 · 2015: 22 · 2014: 18 · 2013: 18 · 2012: 15
- FWCI
- 10.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Pharmacology Biochemistry and Behavior (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (T32DA007027, P01DA009789, P01DA017259, R01 DA015683, R01DA03672)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plant Extracts Effects
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- endocannabinoids, FAAH inhibition, MAGL inhibition, anandamide, 2-arachidonoylglycerol, anxiety-like behavior, marble burying, obsessive-compulsive disorder, JZL184, diazepam, rimonabant, CB1 receptor, tetrahydrocannabinol, locomotor activity
- MeSH terms
- Rimonabant, Fatty Acid Amide Hydrolases, Amidohydrolases, Animals, Anxiety Disorders, Diazepam, Disease Models, Animal, Enzyme Inhibitors, Male, Mice, Inbred C57BL, Monoacylglycerol Lipases, Obsessive-Compulsive Disorder, Piperidines, Pyrazoles, Dronabinol, Anti-Anxiety Agents, Receptor, Cannabinoid, CB1, Mice, Benzodioxoles, Cannabinoid Receptor Modulators, Endocannabinoids
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