title: Inhibition of mTOR kinase via rapamycin blocks persistent predator stress-induced hyperarousal.
abstract: Traumatic, stressful life events are thought to trigger acquired anxiety disorders such as post-traumatic stress disorder (PTSD). Recent data suggests that the mammalian target of rapamycin (mTOR) plays a key role in the formation of traumatic memories. The predator stress paradigm allows us to determine whether mTOR mediates the formation of both context-dependent (associative) and context-independent (non-associative) fear memories. Predator stress involves an acute, unprotected exposure of a rat to a cat which causes long-lasting non-associative fear memories manifested as generalized hyperarousal and increased anxiety-like behavior. Here, we show that rapamycin, an mTOR inhibitor, attenuates predator stress-induced hyperarousal, lasting at least three weeks. In addition, rapamycin blocks a subset of anxiety-like behaviors as measured in the elevated plus maze and hole board. Furthermore, when re-exposed to the predator stress context, rapamycin-treated stressed rats showed increased activity compared to vehicle controls suggesting that rapamycin blocks predator stress-induced associative fear memory. Taken together with past research, our results indicate that mTOR regulation of protein translation is required for the formation of both associative and non-associative fear memories. Overall, these data suggest that mTOR activation may contribute to the development of acquired anxiety disorders such as PTSD.
authors.affiliation: Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave., St. John's, Newfoundland, Canada A1B 3X9.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Fifield
authors.forename: Mark
authors.initials: M
authors.lastname: Hebert
authors.forename: Rebecca
authors.initials: R
authors.lastname: Angel
authors.forename: Robert
authors.initials: R
authors.lastname: Adamec
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Blundell
mesh_terms: D000818:Animals; D001143:Arousal / Q000187:drug effects* / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002415:Cats; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology*; D013313:Stress Disorders, Post-Traumatic / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects* / Q000502:physiology; D013315:Stress, Psychological / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Acquisition; Anxiety; Predator stress; Rapamycin; Startle; mTOR