title: Corticotropin-releasing factor receptor 1 and central heart rate regulation in mice during expression of conditioned fear.
abstract: The present study was performed to 1) determine heart rate (HR) effects mediated through central corticotropin-releasing factor receptor subtypes 1 (CRF(1)) investigate and 2 (CRF(2)) and 2) to 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 brainstem. All HR effects were probably mediated by CRF(1) because injection of the CRF(2)-selective agonist mouse urocortin II was ineffective, and the baseline bradycardia by i.c.v. CRF was preserved in CRF(2)-deficient mice. Injection of various CRF receptor antagonists including the CRF(2)-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 CRF(1) 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.
authors.affiliation: Department of Developmental and Behavioural Neurobiology, Faculty of Earth and Life Sciences (FALW), Vrije Universiteit Amsterdam, De Boelelaan 1087, Room B-256, 1081 HV Amsterdam, The Netherlands. oliver@cncr.vu.nl
authors.forename: Oliver
authors.initials: O
authors.lastname: Stiedl
authors.forename: Michael
authors.initials: M
authors.lastname: Meyer
authors.forename: Olaf
authors.initials: O
authors.lastname: Jahn
authors.forename: Sven Ove
authors.initials: SO
authors.lastname: Ogren
authors.forename: Joachim
authors.initials: J
authors.lastname: Spiess
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology*; D001933:Brain Stem / Q000737:chemistry; D003213:Conditioning, Psychological / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D005239:Fear / Q000502:physiology*; D005260:Female; D006339:Heart Rate; D007276:Injections, Intraventricular; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009478:Neuropeptide Y / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D054832:Urocortins; D000099052:CRF Receptor, Type 1
chemical_list: D009478:Neuropeptide Y; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; C518358:urocortin 2, mouse; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone