Research Article

CRF receptor blockade prevents initiation and consolidation of stress effects on affect in the predator stress model of PTSD

Robert Adamec^a1 c1, Dennis Fougere^a2 and Victoria Risbrough^a3

^a1 Department of Psychology Memorial University, St John's, NL Canada

^a2 Chemical Engineering Department University of New Brunswick, Fredericton, NB, Canada

^a3 Department of Psychiatry, University of California, San Diego, CA, USA

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.

(Received March 24 2009)

(Reviewed May 17 2009)

(Revised July 21 2009)

(Accepted July 27 2009)

(Online publication September 15 2009)

Key Words:

• Anxiety;
• consolidation;
• initiation;
• CRF₁ ;
• predator stress;
• PTSD

Correspondence:

^c1 Address for correspondence: Dr R. Adamec, Department of Psychology Memorial University, St John's, NL, Canada. Tel.: 709 737 7671 Fax: 709 737 2430 Email: radamec@mun.ca