Abstract
Acquisition and storage of aversive memories is one of the basic principles of central nervous systems throughout the animal kingdom1. In the absence of reinforcement, the resulting behavioural response will gradually diminish to be finally extinct. Despite the importance of extinction2, its cellular mechanisms are largely unknown. The cannabinoid receptor 1 (CB1)3 and endocannabinoids4 are present in memory-related brain areas5,6 and modulate memory7,8. 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 memories9. In the basolateral amygdala, endocannabinoids and CB1 were crucially involved in long-term depression of GABA (γ-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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
LeDoux, J. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000)
Davis, M., Falls, W. A. & Gewirtz, J. in Contemporary Issues in Modeling Psychopathology (eds Myslobodsky, M. S. & Weiner, I.) 113–141 (Kluwer Academic, Norwell, 2000)
Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C. & Bonner, T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564 (1990)
Di Marzo, V., Melck, D., Bisogno, T. & De Petrocellis, L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 21, 521–528 (1998)
Marsicano, G. & Lutz, B. Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur. J. Neurosci. 11, 4213–4225 (1999)
Katona, I. et al. Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J. Neurosci. 21, 9506–9518 (2001)
Hampson, R. E. & Deadwyler, S. A. Role of cannabinoid receptors in memory storage. Neurobiol. Dis. 5, 474–482 (1998)
Reibaud, M. et al. Enhancement of memory in cannabinoid CB1 receptor knock-out mice. Eur. J. Pharmacol. 379, R1–R2 (1999)
Falls, W. A., Miserendino, M. J. & Davis, M. Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala. J. Neurosci. 12, 854–863 (1992)
Lu, K. T., Walker, D. L. & Davis, M. Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear-potentiated startle. J. Neurosci. 21, RC162 (2001)
Pertwee, R. G. Cannabinoid receptors and pain. Prog. Neurobiol. 63, 569–611 (2001)
Rodriguez de Fonseca, F., Del Arco, I., Martin-Calderon, J. L., Gorriti, M. A. & Navarro, M. Role of the endogenous cannabinoid system in the regulation of motor activity. Neurobiol. Dis. 5, 483–501 (1998)
Rinaldi-Carmona, M. et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 350, 240–244 (1994)
Petitet, F., Jeantaud, B., Bertrand, P. & Imperato, A. Cannabinoid penetration into mouse brain as determined by ex vivo binding. Eur. J. Pharmacol. 374, 417–421 (1999)
Morgan, M. A., Romanski, L. M. & LeDoux, J. E. Extinction of emotional learning: contribution of medial prefrontal cortex. Neurosci. Lett. 163, 109–113 (1993)
Wilson, R. I. & Nicoll, R. A. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588–592 (2001)
Ohno-Shosaku, T., Maejima, T. & Kano, M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29, 729–738 (2001)
Santini, E., Muller, R. U. & Quirk, G. J. Consolidation of extinction learning involves transfer from NMDA-independent to NMDA-dependent memory. J. Neurosci. 21, 9009–9017 (2001)
El Ghundi, M., O'Dowd, B. F. & George, S. R. Prolonged fear responses in mice lacking dopamine D1 receptor. Brain Res. 892, 86–93 (2001)
Quirk, G. J., Russo, G. K., Barron, J. L. & Lebron, K. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J. Neurosci. 20, 6225–6231 (2000)
Tang, Y. P. et al. Genetic enhancement of learning and memory in mice. Nature 401, 63–69 (1999)
Harris, J. A. & Westbrook, R. F. Evidence that GABA transmission mediates context-specific extinction of learned fear. Psychopharmacology (Berl.) 140, 105–115 (1998)
McGaugh, J. L., Castellano, C. & Brioni, J. Picrotoxin enhances latent extinction of conditioned fear. Behav. Neurosci. 104, 264–267 (1990)
Medina, J. F., Repa, C. J., Mauk, M. D. & LeDoux, J. E. Parallels between cerebellum- and amygdala-dependent conditioning. Nature Rev. Neurosci. 3, 122–131 (2002)
Collins, D. R. & Paré, D. Reciprocal changes in the firing probability of lateral and central medial amygdala neurons. J. Neurosci. 19, 836–844 (1999)
Royer, S., Martina, M. & Paré, D. An inhibitory interface gates impulse traffic between the input and output stations of the amygdala. J. Neurosci. 19, 10575–10583 (1999)
Franklin, K. B. J. & Paxinos, G. The Mouse Brain (Academic, San Diego, 1997)
Di Marzo, V. et al. Levels, metabolism, and pharmacological activity of anandamide in CB(1) cannabinoid receptor knockout mice: evidence for non-CB(1), non-CB(2) receptor-mediated actions of anandamide in mouse brain. J. Neurochem. 75, 2434–2444 (2000)
Rammes, G. et al. Synaptic plasticity in the basolateral amygdala in transgenic mice expressing dominant-negative cAMP response element-binding protein (CREB) in forebrain. Eur. J. Neurosci. 12, 2534–2546 (2000)
Rammes, G., Eder, M., Dodt, H.-U., Kochs, E. & Zieglgänsberger, W. Long-term depression in the basolateral amygdala of the mouse involves the activation of interneurons. Neuroscience 107, 85–97 (2001)
Acknowledgements
S.C.A., T.B. and G.R. contributed equally to this work. We thank S. Bourier, B. Brachvogel and W. Wurst for feeder cells and technical support; K. Pfeffer for E14 embryonic stem cells; K. Rajewsky for Cre deleter mouse line; B. Lüscher for FRT-flanked PGK-neo cassette; M. Wiedemann, H. Dietrich, B. Wölfel, A. Daschner, F. Fezza and A. Rippl for technical assistance, mouse breeding and genotyping; A. Mederer for help with behavioural experiments; F. Holsboer for continuous support; E. Güll for secretarial work; and C. Behl for critically reading the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Marsicano, G., Wotjak, C., Azad, S. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002). https://doi.org/10.1038/nature00839
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nature00839
This article is cited by
-
Effects of cannabidiol on fear conditioning in anxiety disorders: decreased threat expectation during retention, but no enhanced fear re-extinction
Psychopharmacology (2024)
-
Inhibition of fatty acid binding protein-5 in the basolateral amygdala induces anxiolytic effects and accelerates fear memory extinction
Psychopharmacology (2024)
-
Pharmacological diacylglycerol lipase inhibition impairs contextual fear extinction in mice
Psychopharmacology (2024)
-
How depression and antidepressant drugs affect endocannabinoid system?—review of clinical and preclinical studies
Naunyn-Schmiedeberg's Archives of Pharmacology (2024)
-
The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls
EMBO Molecular Medicine (2024)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.