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.

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

“…In the lateral septum, Crhr2 receptor expressing neurons mediate anxiogenic effects (Anthony et al, 2014), however, the effects of septal CRHR2 signaling on sensorimotor gating are unknown. In the present study, predator stress had no further impact on startle, despite previous reports that predator stress increases startle magnitude (Adamec et al, 2010). These data indicate that the predator stress model may be most consistent in modeling the avoidance-like components of PTSD rather than full PTSD-syndrome.…”

“…Session 1 consisted the same parameters as in baseline assessment except that 10 additional pulses (in a pseudorandom order) were presented with houselights on for 2.95 s before the startle stimulus. This session replicated the acoustic startle session previously described for the mouse predator stress model of PTSD (Adamec et al, 2010). To further assess startle habituation and inhibition as measured by PPI, a second session was presented immediately after the first (Session 2 with 65 dB background and lights on).…”

“…As conducted previously, mice were isolated 1 week before predator stress and housed individually for the remainder of the experiment (Adamec et al, 2010), because pilot studies suggested that isolated mice exhibit stronger predator stress effects owing to lower levels of baseline avoidance behaviors.…”

“…Startle reactivity was assessed in Plexiglas chambers (San Diego Instruments, San Diego, CA) as previously described (Adamec et al, 2010;Toth et al, 2014). Briefly, 1 week before stress exposure, baseline startle was assessed over 3 consecutive days using Session 1, which presented 10 105 dB pulses over 50 dB background in dark chambers.…”

“…To test this hypothesis, we induced transient forebrain-specific CRHOE before puberty in double-mutant mice and exposed them to a single traumatic event in adulthood using a well-validated model of PTSD (Adamec et al, 2010;Bakshi et al, 2012). To determine the behavioral sequelae, we assessed PTSD-related symptom clusters, ie, startle reactivity, general and trauma-specific avoidance behaviors.…”