Corticotropin-releasing factor receptor 1 and central heart rate regulation in mice during expression of conditioned fear

The present study was performed to 1) determine heart rate (HR) effects mediated through central corticotropin-releasing factor receptor subtypes 1 (CRF1) and 2 (CRF2) and 2) to investigate the contribution of endogenous CRF to baseline HR and its fear-induced adjustment in freely moving mice. CRF ligands were injected into both lateral ventricles (i.c.v.) 15 min before the presentation of a conditioned auditory fear stimulus (CS). Initial behavioral results suggest an ovine CRF (oCRF)mediated enhanced baseline fear and mildly enhanced conditioned auditory fear. In contrast, i.c.v. injection of oCRF (35-210 ng/mouse) dose-dependently decreased baseline HR, increased HR variability, and attenuated the CS-induced tachycardia. This effect is suggested to depend on a combined activation of sympathetic and parasympathetic activity referred to as enhanced sympathovagal antagonism. An extreme bradycardia was elicited by oCRF injection into the lower brain-stem. All HR effects were probably mediated by CRF1 because injection of the CRF2-selective agonist mouse urocortin II was ineffective, and the baseline bradycardia by i.c.v. CRF was preserved in CRF2-deficient mice. Injection of various CRF receptor antagonists including the CRF2-selective antisauvagine-30 did not affect the conditioned HR response. This finding suggests that endogenous CRF does not contribute to the fear-mediated tachycardia. Thus, the hypothesis of an involvement of CRF in HR responses of mice to acute aversive stimulation is rejected. Pharmacological evidence points at the involvement of CRF1 in enhanced sympathovagal antagonism, a pathological state contributing to elevated cardiac risk, whereas the physiological role of the brain CRF system in cardiovascular regulation remains to be determined.