Structure-related effects of CRF and CRF-derived peptides: dissociation of behavioral, endocrine and autonomic activity.
Two C-terminal and one N-terminal peptide fragments derived from corticotropin-releasing factor (CRF-1-41), CRF-28-41, CRF-34-41, and CRF-1-8, and the CRF receptor antagonist alpha-helical CRF-9-41 (alpha hCRF) were evaluated for their behavioral, endocrine and autonomic nervous effects in rats. To this purpose, three different approaches were used. First, rats were tested in a passive avoidance behavioral (PAB) task after intracerebroventricular (i.c.v.) injection the peptides at five different doses. I.c.v. CRF-1-41 was found to attenuate PAB. The effects of CRF-1-41 on PAB were completely antagonized by i.c.v. pretreatment with alpha hCRF. When given as a sole treatment, the antagonist produced a bimodal effect on PAB. At low doses, alpha hCRF tended to facilitate PAB, while high doses of the antagonist significantly attenuated PAB. Both CRF fragments showed behavioral effects similar to CRF-1-41. Of all peptides tested, CRF-34-41 was found to most attenuate PAB at both retention tests. In a second experiment, the behaviorally most potent fragment CRF-34-41 was compared to CRF-1-41 for its adrenocorticotropic activity after iv injection in pentobarbital-anesthetized rats. Treatment with CRF-1-41, in a dose-related fashion, produced a significant rise in plasma ACTH, whereas CRF-34-41 was without effect. Finally, the effect of i.c.v. injected CRF-1-41 and CRF fragments on heart rate (HR) and gross activity was measured in conscious rats in their home cages during a 60-min period, using a wireless telemetry system. Concomitantly, the occurrence of grooming behavior was recorded. During the first 10 min after i.c.v. treatment, of all peptides tested, CRF-34-41 produced the most marked increase in HR, which remained significant only during the first 30 min of recording. CRF-28-41 induced a non significant transient tachycardia. The parent molecule CRF-1-41 also induced an immediate, significant tachycardia but this effect lasted longer than 60 min. The N-terminal CRF-1-8 remained without effect. No significant effects on gross activity were observed with the two short C-terminal peptides, whereas i.c.v. injected CRF-1-41 induced excessive grooming behavior. A significant grooming response was also recorded in rats given CRF-34-41 fragment, but not in those treated with CRF-28-41 or CRF-1-8.(ABSTRACT TRUNCATED AT 400 WORDS)
Diamant
M
M
Rudolf Magnus Institute, Department of Medical Pharmacology, Faculty of Medicine, University of Utrecht, The Netherlands.
de Wied
D
D
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004702:Endocrine Glands / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone