Corticotropin-releasing factor and noradrenergic signalling exert reciprocal control over startle reactivity.

Corticotropin-releasing factor (CRF) and norepinephrine (NE) levels are altered in post-traumatic stress disorder and may be related to symptoms of hyperarousal, including exaggerated startle, in these patients. In animals, activation of both systems modulates anxiety behaviours including startle plasticity; however, it is unknown if they exert their actions orthogonally or dependently. We tested the hypothesis that NE receptor activation is required for CRF effects on startle and that CRF1 receptor activation is required for NE effects on startle. The study examined the effects of: (1) α2 agonist clonidine (0.18 mg/kg i.p.), α1 antagonist prazosin (0.8 mg/kg), and ß1/2 antagonist propranolol (0.8, 8.0 mg/kg) pretreatment on ovine-CRF (oCRF)- (0.6 nmol) induced increases in startle reactivity and disruption of prepulse inhibition (PPI); (2) α2 antagonist atipamezole (1-30 mg/kg) and α1 agonist cirazoline (0.025-1.0 mg/kg) treatment on startle; (3) CRF1 antagonist (antalarmin, 14 mg/kg) pretreatment on atipamezole- (10.0 mg/kg) induced increases in startle. oCRF robustly increased startle and reduced PPI. Pretreatment with clonidine or prazosin, but not propranolol, blocked oCRF-induced increases in startle but had no effect on oCRF-induced disruptions in PPI. Atipamezole treatment increased startle, which was partially attenuated by CRF1 antagonist pretreatment. Cirazoline treatment did not increase startle. These findings suggest that CRF modulation of startle, but not PPI, requires activation of α1 adrenergic receptors, while CRF1 activation also contributes to NE modulation of startle. These data support a bi-directional model of CRF-NE modulation of stress responses and suggest that both systems must be activated to induce stress effects on startle reactivity.