Abstract
The present study was performed to 1) determine heart rate (HR) effects mediated through central corticotropin-releasing factor receptor subtypes 1 (CRF1) investigate and 2 (CRF2) 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 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.
Footnotes
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This study has been supported by the Max Planck Society (J.S., M.M., O.J., O.S.), Karolinska Institutets fonder (O.S., S.O.Ö.) and the Wenner-Gren Foundations (O.S.), and the Vrije Universiteit (O.S.).
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doi:10.1124/jpet.104.075820.
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ABBREVIATIONS: CRF, corticotropin-releasing factor; CRF1, CRF receptor subtype 1; CRF2, CRF receptor subtype 2; HR, heart rate; CS, conditioned stimulus; CRFBP, CRF binding protein; HRV, heart rate variability; RMSSD, square root of the mean of the sum of successive RR interval differences; ANOVA, analysis of variance; [Glu11,16]Ast, [Glu11,16]astressin; h/rCRF, human/rat CRF; h/rCRF6–33, CRF binding protein inhibitor; aCSF, artificial cerebrospinal fluid; αhelCRF, α-helical CRF9–41; aSvg-30, antisauvagine-30; mUcnII, mouse urocortin II; oCRF, ovine CRF; DMNV, dorsal motor nucleus of the nervus vagus; AP, anterior-posterior; US, unconditioned stimulus; NPY, neuropeptide Y; rCRF1-NT, N terminus of rat CRF receptor 1; ΔHR, CS-induced HR increase; DPheCRF, [DPhe12Nle21,38]human/rat CRF12–41; bpm, beats per minute; oCRF1–41(OH), C-terminally desamidated oCRF; CP-154,526, butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]-pyrimidin-4-yl]ethylamine.
- Received August 10, 2004.
- Accepted November 8, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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