title: The involvement of cannabinoids and mTOR in the reconsolidation of an emotional memory in the hippocampal-amygdala-insular circuit.
abstract: 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.
authors.affiliation: Department of Psychology, University of Haifa, Haifa 3498838, Israel.
authors.forename: Salman
authors.initials: S
authors.lastname: Zubedat
authors.affiliation: Department of Psychology, University of Haifa, Haifa 3498838, Israel. Electronic address: irit.akirav@gmail.com.
authors.forename: Irit
authors.initials: I
authors.lastname: Akirav
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D048588:Benzoxazines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D002186:Cannabinoids / Q000819:agonists / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D004644:Emotions / Q000187:drug effects / Q000502:physiology*; D005106:Exploratory Behavior / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Cannabinoids; Extinction; Fear memory; Rapamycin; Reconsolidation; mTOR