Abstract
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.
MeSH terms
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Adrenocorticotropic Hormone / blood
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Animals
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Anti-Anxiety Agents / pharmacokinetics*
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Anxiety / drug therapy*
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Anxiety / metabolism
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Anxiety / physiopathology
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Behavior, Animal / drug effects
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Behavior, Animal / physiology
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Binding Sites / drug effects
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Binding Sites / physiology
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Binding, Competitive / drug effects
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Binding, Competitive / physiology
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Brain / drug effects*
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Brain / metabolism
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Brain / physiopathology
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Corticosterone / blood
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Corticotropin-Releasing Hormone / metabolism*
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Corticotropin-Releasing Hormone / pharmacology
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Dose-Response Relationship, Drug
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Drug Interactions / physiology
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Male
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Maze Learning / drug effects
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Maze Learning / physiology
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Pituitary-Adrenal System / drug effects
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Pituitary-Adrenal System / physiology
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Pyrimidines / pharmacokinetics*
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Rats
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Rats, Wistar
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Reaction Time / drug effects
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Reaction Time / physiology
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Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
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Receptors, Corticotropin-Releasing Hormone / metabolism
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Stress, Physiological / drug therapy*
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Stress, Physiological / metabolism
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Stress, Physiological / physiopathology
Substances
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Anti-Anxiety Agents
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Pyrimidines
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R 121919
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Receptors, Corticotropin-Releasing Hormone
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CRF receptor type 1
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Adrenocorticotropic Hormone
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Corticotropin-Releasing Hormone
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Corticosterone