Characterization of a novel and potent corticotropin-releasing factor antagonist in rats.
Abstract
The present study examined the ability of two analogs of human/rat corticotropin-releasing factor (h/rCRF), [Met18, Lys23, Glu27,29,40, Ala32,41, Leu33,36,38] h/rCRF9-41 (alpha-hel CRF9-41) and [D-Phe12, Nle21,38, C alpha MeLeu37] h/rCRF12-41 (D-Phe CRF12-41), to antagonize CRF- and stress-induced behavioral changes in rats. The potency and duration of action of D-Phe CRF12-41 in vivo was compared with that of alpha-hel CRF9-41, the most effective CRF antagonist studied to date. When administered i.c.v., both CRF antagonists dose-dependently reduced the locomotor activity induced by rat CRF (0.5 microgram/rat i.c.v.) and attenuated the social stress-induced anxiogenic-like effect, as measured by the elevated plus-maze. However D-Phe CRF12-41 was 5 times more potent and remained effective for a longer period (> 1.5 hr) than alpha-hel CRF9-41. High doses of alpha-hel CRF9-41 (25 micrograms/rat), by itself, exhibited weak agonist effects, which were not observed with D-Phe CRF12-41 at the same doses. These results demonstrate that a N-terminus-shortened CRF antagonist that encompasses the substitution D-Phe12 has significantly higher biological potency and an extended duration of action without intrinsic agonist effects in these in vivo systems. The availability of potent and effective CRF antagonists will provide valuable tools for exploring the functional role of brain CRF and may ultimately lead to an understanding of the biological basis of stress-related illnesses.
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CRF administration into rat brain reproduces many stress-like behavioral responses, while CRF antagonists reduce or prevent stress responses.
“Administration of CRF into the brain of rats reproduces many different behavioral responses analogous to stress, while CRF antagonists reduce or prevent stress responses (Dunn and Berridge 1990; Heinrichs et al 1994; Menzaghi et al 1994).”
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- Authors
- Menzaghi, F., Howard, R. L., Heinrichs, S. C., Vale, W., Rivier, J., & Koob, G. F.
- Affiliations
- Scripps Research Institute (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 1994-05
- Volume
- 269
- Issue
- 2
- Pages
- 564-572
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2151542810
- Cited by
- 181
- References
- 0
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 1 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 6 · 2016: 3 · 2014: 1 · 2013: 2 · 2012: 6
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- corticotropin-releasing factor, CRF antagonist, stress-induced anxiety, social stress, locomotor activity, elevated plus maze, intracerebroventricular administration, duration of action, stress-related disorders
- MeSH terms
- Amino Acid Sequence, Animals, Anxiety, Cerebral Ventricles, Corticotropin-Releasing Hormone, Dose-Response Relationship, Drug, Humans, Locomotion, Male, Molecular Sequence Data, Peptide Fragments, Rats, Wistar, Rats
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