Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation
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Endocannabinoid (eCB) signaling has been heavily implicated in the modulation of anxiety and depressive behaviors and emotional learning. However, the role of the most-abundant endocannabinoid 2-arachidonoylglycerol (2-AG) in the physiological regulation of affective behaviors is not well understood. Here, we show that genetic deletion of the 2-AG synthetic enzyme diacylglycerol lipase α (DAGLα) in mice reduces brain, but not circulating, 2-AG levels. DAGLα deletion also results in anxiety-like and sex-specific anhedonic phenotypes associated with impaired activity-dependent eCB retrograde signaling at amygdala glutamatergic synapses. Importantly, acute pharmacological normalization of 2-AG levels reverses both phenotypes of DAGLα-deficient mice. These data suggest 2-AG deficiency could contribute to the pathogenesis of affective disorders and that pharmacological normalization of 2-AG signaling could represent an approach for the treatment of mood and anxiety disorders.
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In mice lacking the 2-AG synthesising enzyme diacylglycerol lipase, anxiety-related behaviour is enhanced.
“and in mice lacking the 2-AG synthesising enzyme diacylglycerol lipase anxiety-related behaviour is enhanced (Jenniches et al., 2016;Shonesy et al., 2014).”
From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Shonesy et al., 2014
Mice with genetic deletion of DAGL and reductions in 2-AG signaling show increases in anxiety-like behavior.
“in mice with genetic deletion of DALG and reductions in 2-AG signaling, increases in anxiety-like behavior are evident (Jenniches et al., 2016; Shonesy et al., 2014).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Shonesy et al., 2014
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- Authors
- Shonesy, B. C., Bluett, R. J., Ramikie, T. S., Báldi, R., Hermanson, D. J., Kingsley, P. J., Marnett, L. J., Winder, D. G., Colbran, R. J., & Patel, S.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Patel, Sachin
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 9
- Issue
- 5
- Pages
- 1644-1653
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4268380
- OpenAlex
- W2058418000
- Cited by
- 155
- References
- 52
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 12 · 2023: 13 · 2022: 10 · 2021: 22 · 2020: 17 · 2019: 7 · 2018: 13 · 2017: 16 · 2016: 13 · 2015: 14
- FWCI
- 10.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Vanderbilt University
- National Institutes of Health
- National Institute of Mental Health (R01MH100096, F31MH106192, K08MH090412, T32MH065215)
- National Institute on Drug Abuse (DA031572, F31DA031572)
- National Cancer Institute (CA68485, P30CA068485)
- National Institute of General Medical Sciences (GM 15431, P01GM015431)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 20593, P30DK020593)
- National Institute of Neurological Disorders and Stroke (R01NS078291)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD015052, HD 15052)
- 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
- 2-arachidonoylglycerol, endocannabinoid signaling, diacylglycerol lipase alpha, anxiety-like behavior, anhedonia, sex differences, retrograde signaling, mood disorders
- MeSH terms
- Amygdala, Animals, Anxiety, Arachidonic Acids, Depression, Disease Models, Animal, Female, Glycerides, Male, Synaptic Transmission, Mice, Knockout, Glutamic Acid, Endocannabinoids
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