The endogenous cannabinoid system controls extinction of aversive memories
Abstract
Acquisition and storage of aversive memories is one of the basic principles of central nervous systems throughout the animal kingdom. In the absence of reinforcement, the resulting behavioural response will gradually diminish to be finally extinct. Despite the importance of extinction, its cellular mechanisms are largely unknown. The cannabinoid receptor 1 (CB1) and endocannabinoids are present in memory-related brain areas and modulate memory. Here we show that the endogenous cannabinoid system has a central function in extinction of aversive memories. CB1-deficient mice showed strongly impaired short-term and long-term extinction in auditory fear-conditioning tests, with unaffected memory acquisition and consolidation. Treatment of wild-type mice with the CB1 antagonist SR141716A mimicked the phenotype of CB1-deficient mice, revealing that CB1 is required at the moment of memory extinction. Consistently, tone presentation during extinction trials resulted in elevated levels of endocannabinoids in the basolateral amygdala complex, a region known to control extinction of aversive memories. In the basolateral amygdala, endocannabinoids and CB1 were crucially involved in long-term depression of GABA (gamma-aminobutyric acid)-mediated inhibitory currents. We propose that endocannabinoids facilitate extinction of aversive memories through their selective inhibitory effects on local inhibitory networks in the amygdala.
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Following binding to central nervous system receptors such as CB1, endocannabinoids reduce anxiety and increase food intake.
“Following their binding to central nervous system receptors (e.g.CB1 receptors), endocannabinoids have been shown, e.g., to reduce anxiety (Marsicano et al., 2002;Lutz et al., 2015) and increase food intake (Di Marzo et al., 2001).”
From Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans (2016) · cites this paper as Marsicano et al., 2002
There is an emerging body of evidence demonstrating an important role for CB1 receptor-mediated endocannabinoid signaling in the extinction of aversive memories.
“Moreover, there is an emerging body of evidence demonstrating an important role for CB1 receptor-mediated endocannabinoid signaling in the extinction of aversive memories8.”
From Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: A positron emission tomography study (2013) · cites this paper as [8]
Elevated EC signaling during stress regulates the extinction of traumatic memories.
“As part of this protective role under aversive conditions, elevated EC signaling during stress has been shown to dampen the development of anxiety [12] and to regulate the encoding [13], retrieval [14] and extinction [15] of traumatic memories.”
From Plasma concentrations of endocannabinoids and related primary fatty acid amides in patients with post-traumatic stress disorder (2013) · cites this paper as [15]
Inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA-CB1 receptor signaling and synaptic plasticity in the BLA.
“Additionally, inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA–CB1 (cannabinoid type 1) receptor signaling and synaptic plasticity in the BLA.”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [86]
Extinction training in mice elevates AEA and 2-AG levels in the BLA.
“Marsicano and colleagues reported elevated AEA and 2-AG BLA levels after extinction training in mice [86]”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [86]
A CB1R-dependent form of synaptic plasticity in the BLA, long-term depression of inhibitory GABAergic transmission (LTDi), is enhanced by FAAH knockout and by the FAAH inhibitor AM3506 at doses that promote extinction.
“One notable finding is that a CB1R-dependent form of synaptic plasticity in BLA [51,86], long-term depression of inhibitory GABAergic transmission (LTDi), is enhanced by FAAH KO [51] and by the FAAH inhibitor AM3506 at doses that promote extinction [50].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [86]
CB1R knockout or systemic antagonist (SR141716A) administration produces impairments in extinction learning but not fear conditioning.
“and produced impairments in extinction learning (but not fear conditioning) by CB1R KO or systemic antagonist (SR141716A) administration [28,86]”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [86]
AEA released during extinction relieves a tonic inhibitory brake on BLA output neurons necessary for the encoding of extinction memories.
“This suggests a scheme in which AEA released during extinction relieves a tonic inhibitory brake on BLA output neurons [50,51,86] necessary for the encoding of extinction memories [102] (Figure 2).”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [86]
The cannabinoid system is part of the complex circuitry that regulates anxiety and stress and is a crucial mediator of emotional learning.
“The cannabinoid system is part of the complex circuitry that regulates anxiety and stress and is a crucial mediator of emotional learning (Marsicano et al, 2002;Viveros et al, 2005;Patel et al, 2005Patel et al, , 2005a; Laviolette and Grace, 2006;Varvel et al, 2007;Ganon-Elazar and Akirav, 2009;Lutz, 2009;Hill et al, 2009;Abush and Akirav, 2010;Akirav, 2011).”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Marsicano et al, 2002
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- Authors
- Marsicano, G., Wotjak, C. T., Azad, S. C., Bisogno, T., Rammes, G., Cascio, M. G., Hermann, H., Tang, J., Hofmann, C., Zieglgänsberger, W., Di Marzo, V., & Lutz, B.
- Affiliations
- Max Planck Institute of Psychiatry (DE)
- LMU Klinikum (DE)
- Istituto di Chimica Biomolecolare (IT)
- Helmholtz Munich (DE)
- Corresponding author
- Lutz, Beat
- Venue
- Nature
- Published
- 2002-08
- Volume
- 418
- Issue
- 6897
- Pages
- 530-534
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1982291289
- Cited by
- 1,728
- References
- 30
- Citations by year
- 2026: 22 · 2025: 39 · 2024: 41 · 2023: 48 · 2022: 60 · 2021: 61 · 2020: 60 · 2019: 70 · 2018: 64 · 2017: 77 · 2016: 75 · 2015: 87 · 2014: 90 · 2013: 87 · 2012: 85
- FWCI
- 42.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- endocannabinoid system, CB1 receptor, CB1 knockout mice, fear extinction, auditory fear conditioning, basolateral amygdala, long-term depression, GABAergic inhibition, SR141716A, memory consolidation, inhibitory neural networks
- MeSH terms
- Rimonabant, Acoustic Stimulation, Amygdala, Animals, Cannabinoids, Conditioning, Classical, Electrophysiology, Extinction, Psychological, Fear, gamma-Aminobutyric Acid, Male, Memory, Mice, Inbred C57BL, Neuronal Plasticity, Neurons, Piperidines, Pyrazoles, Receptors, Drug, Synapses, Gene Deletion, Mice, Knockout, Receptors, Cannabinoid, Mice, Cannabinoid Receptor Modulators, In Vitro Techniques
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