Letters to Nature

Nature 418, 530-534 (1 August 2002) | doi:10.1038/nature00839; Received 24 December 2001; Accepted 16 April 2002

The endogenous cannabinoid system controls extinction of aversive memories

Giovanni Marsicano1,8, Carsten T. Wotjak2,8, Shahnaz C. Azad3,3, Tiziana Bisogno5, Gerhard Rammes3, Maria Grazia Cascio5, Heike Hermann1, Jianrong Tang2, Clementine Hofmann6,7, Walter Zieglgänsberger3, Vincenzo Di Marzo5 & Beat Lutz1

  1. Molecular Genetics of Behaviour, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany
  2. Neuronal Plasticity/Mouse Behaviour, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany
  3. Neuropharmacology Group, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany
  4. Clinic of Anaesthesiology, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377 Munich, Germany
  5. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Via Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy
  6. Institute of Mammalian Genetics, GSF National Research Center for Environment and Health, Ingolstädter Landstrasse 1, 85764 Neuherberg-Munich, Germany
  7. These authors contributed equally to this work
  8. Present address: Molecular Neurogenetics Group, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany.

Correspondence to: Beat Lutz1 Correspondence and requests for materials should be addressed to B.L. (e-mail: Email: lutz@mpipsykl.mpg.de).

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 (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.