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Neuropsychopharmacology (2002) 27 194-202.10.1038/S0893-133X(02)00299-3
Brain Penetrance, Receptor Occupancy and Antistress In Vivo Efficacy of a Small Molecule Corticotropin Releasing Factor Type I Receptor Selective Antagonist
Stephen C Heinrichs Ph.D, Errol B De Souza Ph.D, Gery Schulteis Ph.D, Jeanette L Lapsansky and Dimitri E Grigoriadis Ph.D |
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Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121 USA
Correspondence: Dr Stephen C Heinrichs, Department of Psychology, Boston College, McGuinn Hall, 140 Commonwealth Avenue, Chestnut Hill, MA 02467. Tel.: 617-552-0852; Fax: 617-552-0523; E-mail: stephen.heinrichs@bc.edu
Current address: Aventis Pharmaceuticals, Route 202-206, PO Box 6800, Bridgewater, NJ 08807-0800
Current address: UC San Diego, Department of Anesthesiology, School of Medicine, 3350 La Jolla Drive, San Diego, CA 92161-5085
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ABSTRACT
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The present studies were designed to evaluate the competitive binding properties and functional effects of a novel nonpeptide CRF1 receptor antagonist, R121919. R121919 administered in doses of 0.63 to 20 mg/kg p.o. 60 min pretest in Wistar rats dose dependently attenuated the swim stress-induced anxiogenic-like behavior in the elevated plus-maze model of anxiety. Moreover, receptor autoradiography revealed that R121919 dose-dependently occupied brain CRF1 receptors in subjects tested in the plus-maze experiment. Orally administered doses of up to 20 mg/kg R121919 also blunted basal and swim stress-induced pituitary-adrenocortical activation, produced additional anxiolytic-like behavioral actions in the defensive withdrawal and defensive burying paradigms, and functionally antagonized the locomotor stimulatory properties of exogenously administered CRF. Taken together, these results suggest that the anxiolytic-like efficacy of R121919 in attenuating the stress-, novelty-, shock-, and CRF-induced increases in behavioral arousal is correlated with competitive blockade of central CRF1 receptors.
Keywords: CRF; Stress; Anxiety; Pituitary-adrenal; Axiolytic |
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