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The endogenous cannabinoid system controls extinction of aversive memories

Author

Listed:
  • Giovanni Marsicano

    (Max Planck Institute of Psychiatry)

  • Carsten T. Wotjak

    (Max Planck Institute of Psychiatry)

  • Shahnaz C. Azad

    (Max Planck Institute of Psychiatry
    Ludwig-Maximilians-University)

  • 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
    Max Planck Institute of Psychiatry)

  • Walter Zieglgänsberger

    (Max Planck Institute of Psychiatry)

  • Vincenzo Di Marzo

    (Institute of Biomolecular Chemistry, CNR)

  • Beat Lutz

    (Max Planck Institute of Psychiatry)

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.

Suggested Citation

  • Giovanni Marsicano & Carsten T. Wotjak & Shahnaz C. Azad & Tiziana Bisogno & Gerhard Rammes & Maria Grazia Cascio & Heike Hermann & Jianrong Tang & Clementine Hofmann & Walter Zieglgänsberger & Vincen, 2002. "The endogenous cannabinoid system controls extinction of aversive memories," Nature, Nature, vol. 418(6897), pages 530-534, August.
  • Handle: RePEc:nat:nature:v:418:y:2002:i:6897:d:10.1038_nature00839
    DOI: 10.1038/nature00839
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    Cited by:

    1. Danielle Hen-Shoval & Aron Weller & Abraham Weizman & Gal Shoval, 2022. "Examining the Use of Antidepressants for Adolescents with Depression/Anxiety Who Regularly Use Cannabis: A Narrative Review," IJERPH, MDPI, vol. 19(1), pages 1-19, January.
    2. Emma Puighermanal & Marta Luna-Sánchez & Alejandro Gella & Gunter van der Walt & Andrea Urpi & María Royo & Paula Tena-Morraja & Isabella Appiah & Maria Helena de Donato & Fabien Menardy & Patrizia Bi, 2024. "Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Stéphane Leon & Vincent Simon & Thomas H. Lee & Lukas Steuernagel & Samantha Clark & Nasim Biglari & Thierry Lesté-Lasserre & Nathalie Dupuy & Astrid Cannich & Luigi Bellocchio & Philippe Zizzari & Ca, 2024. "Single cell tracing of Pomc neurons reveals recruitment of ‘Ghost’ subtypes with atypical identity in a mouse model of obesity," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Paula Gómez-Sotres & Urszula Skupio & Tommaso Dalla Tor & Francisca Julio-Kalajzic & Astrid Cannich & Doriane Gisquet & Itziar Bonilla-Del Rio & Filippo Drago & Nagore Puente & Pedro Grandes & Luigi B, 2024. "Olfactory bulb astrocytes link social transmission of stress to cognitive adaptation in male mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Irene B. Maroto & Carlos Costas-Insua & Coralie Berthoux & Estefanía Moreno & Andrea Ruiz-Calvo & Carlos Montero-Fernández & Andrea Macías-Camero & Ricardo Martín & Nuria García-Font & José Sánchez-Pr, 2023. "Control of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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