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The endogenous cannabinoid system controls extinction of aversive memories


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.

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Figure 1: Impaired extinction of aversive memory in an auditory fear-conditioning task of CB1-/- mice (filled circles) as compared to their CB1+/+ littermates (open circles).
Figure 2: CB1 antagonist SR141716A impairs short-term and long-term extinction, but not acquisition and consolidation of aversive memories.
Figure 3: Re-exposure to the tone 24?h after conditioning causes increased endocannabinoid levels in the basolateral amygdala complex (BLAC) but not the medial prefrontal cortex (mPFC) of C57BL/6J mice.
Figure 4: Endogenous cannabinoid system and synaptic plasticity in the basolateral amygdala.

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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.

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Correspondence to Beat Lutz.

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Marsicano, G., Wotjak, C., Azad, S. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002).

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