The endogenous cannabinoid system controls extinction of aversive memories

Giovanni Marsicano, Carsten T. Wotjak, Shahnaz C. Azad, Tiziana Bisogno, Gerhard Rammes, Maria Grazia Cascio, Heike Hermann, Jianrong Tang, Clementine Hofmann, Walter Zieglgänsberger, Vincenzo Di Marzo and Beat Lutz ()
Additional contact information
Giovanni Marsicano: Max Planck Institute of Psychiatry
Carsten T. Wotjak: Max Planck Institute of Psychiatry
Shahnaz C. Azad: Max Planck Institute of Psychiatry
Tiziana Bisogno: Institute of Biomolecular Chemistry, CNR
Gerhard Rammes: Max Planck Institute of Psychiatry
Maria Grazia Cascio: Institute of Biomolecular Chemistry, CNR
Heike Hermann: Max Planck Institute of Psychiatry
Jianrong Tang: Max Planck Institute of Psychiatry
Clementine Hofmann: Institute of Mammalian Genetics, GSF National Research Center for Environment and Health
Walter Zieglgänsberger: Max Planck Institute of Psychiatry
Vincenzo Di Marzo: Institute of Biomolecular Chemistry, CNR
Beat Lutz: Max Planck Institute of Psychiatry

Nature, 2002, vol. 418, issue 6897, 530-534

Abstract: 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.

Date: 2002
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DOI: 10.1038/nature00839

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