The involvement of cannabinoids and mTOR in the reconsolidation of an emotional memory in the hippocampal–amygdala–insular circuit

Salman Zubedat, Irit Akirav

Research output: Contribution to journalArticlepeer-review


Memory reconsolidation is the process in which reactivated long-term memory becomes transiently sensitive to amnesic agents. We evaluated the ability of post reactivation administration of the mTOR inhibitor rapamycin, separately and in combination with the cannabinoid CB1/2 receptor agonist WIN55,212-2 (WIN), given systemically or specifically into the hippocampal CA1 area, basolateral amygdala (BLA) or insular cortex (IC), to reduce inhibitory avoidance fear in rats. Systemic administration of rapamycin after reactivation of fear memory impaired reconsolidation and facilitated extinction. A combined treatment with WIN and rapamycin resulted in similar effects. WIN injected systemically facilitated extinction, with no effect on reconsolidation. WIN alone and with rapamycin also decreased anxiety-like behavior. Further, when spontaneous recovery was tested, the WIN+rapamycin group did not demonstrate recovery of fear which can occur spontaneously after the passage of time. Rapamycin and WIN had differential effects on reconsolidation and extinction when microinjected into the CA1, BLA and IC. Furthermore, exposure to shock increased p70s6K activation in the BLA, indicating activation by mTOR. Treatment with rapamycin, WIN or WIN+rapamycin decreased activation and there was a strong positive correlation between fear retrieval and p70s6K activation in the BLA, suggesting that enhanced fear retrieval is associated with enhanced p70s6K activation. Taken together, the results suggest that rapamycin or a combined treatment that involves blocking mTOR and activating cannabinoids may be a promising pharmacological approach for the attenuation of reactivated emotional memories, and thus, it could represent a potential treatment strategy for disorders associated with traumatic memories.

Original languageEnglish
Pages (from-to)336-349
Number of pages14
JournalEuropean Neuropsychopharmacology
Issue number4
StatePublished - Apr 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier B.V. and ECNP


  • Cannabinoids
  • Extinction
  • Fear memory
  • Rapamycin
  • Reconsolidation
  • mTOR

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Psychiatry and Mental health
  • Pharmacology (medical)
  • Biological Psychiatry
  • Pharmacology


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