title: CRF receptor blockade prevents initiation and consolidation of stress effects on affect in the predator stress model of PTSD.
abstract: Post traumatic stress disorder (PTSD) is a chronic anxiety disorder initiated by an intensely threatening, traumatic event. There is a great need for more efficacious pharmacotherapy and preventive treatments for PTSD. In animals, corticotropin-releasing factor (CRF) and the CRF1 receptor play a critical role in behavioural and neuroendocrine responses to stress. We tested the hypothesis that CRF1 activation is required for initiation and consolidation of long-term effects of trauma on anxiety-like behaviour in the predator exposure (predator stress) model of PTSD. Male C57BL6 mice were treated with the selective CRF1 antagonist CRA0450 (2, 20 mg/kg) 30 min before or just after predator stress. Long-term effects of stress on rodent anxiety were measured 7 d later using acoustic startle, elevated plus maze (EPM), light/dark box, and hole-board tests. Predator stress increased startle amplitude and delayed startle habituation, increased time in and decreased exits from the dark chamber in the light/dark box test, and decreased risk assessment in the EPM. CRF1 antagonism had limited effects on these behaviours in non-stressed controls, with the high dose decreasing risk assessment in the EPM. However, in stressed animals CRF1 antagonism blocked initiation and consolidation of stressor effects on startle, and returned risk assessment to baseline levels in predator-stressed mice. These findings implicate CRF1 activation in initiation and post-trauma consolidation of predator stress effects on anxiety-like behaviour, specifically on increased arousal as measured by exaggerated startle behaviours. These data support further research of CRF1 antagonists as potential prophylactic treatments for PTSD.
authors.affiliation: Department of Psychology Memorial University, St John's, NL, Canada. radamec@mun.ca
authors.forename: Robert
authors.initials: R
authors.lastname: Adamec
authors.forename: Dennis
authors.initials: D
authors.lastname: Fougere
authors.forename: Victoria
authors.initials: V
authors.lastname: Risbrough
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000221:Adaptation, Ocular / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001557:Benzenesulfonates / Q000008:administration & dosage; D002415:Cats; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011804:Quinolines / Q000008:administration & dosage; D011897:Random Allocation; D011930:Reaction Time / Q000187:drug effects; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects; D013313:Stress Disorders, Post-Traumatic / Q000209:etiology* / Q000517:prevention & control*; D013315:Stress, Psychological / Q000150:complications*; D013997:Time Factors; D000099052:CRF Receptor, Type 1
chemical_list: C491550:1-(8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide benzenesulfonate; D001557:Benzenesulfonates; D011804:Quinolines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1