Pharmacological Evidence Supporting a Role for Central Corticotropin-Releasing Factor2 Receptors in Behavioral, but not Endocrine, Response to Environmental Stress

doi:10.1124/jpet.302.1.145

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Vol. 302, Issue 1, 145-152, July 2002

Pharmacological Evidence Supporting a Role for Central Corticotropin-Releasing Factor₂ Receptors in Behavioral, but not Endocrine, Response to Environmental Stress

Mary Ann Pelleymounter¹, Margaret Joppa, Nicholas Ling and Alan C. Foster

Neurocrine Biosciences, Inc., San Diego, California

Corticotropin-releasing factor (CRF) is one of the principle components of the stress response. The physiological effectsof CRF are mediated by two receptor subtypes, CRF₁ and CRF₂. Recentdata obtained with the selective CRF₂ antagonist antisauvagine-30(ASV-30) has begun to suggest that both CRF receptor subtypesmay play a role in stress-related behaviors. Exactly how thesetwo receptor subtypes interact to modulate the behavioral andendocrine responses to stress is not clear, however. We have attemptedto understand the role of the CRF₂ receptor in the behavioraland endocrine responses to stress by comparing the effects ofASV-30 with the mixed CRF₁/CRF₂ receptor antagonist astressin.Centrally administered ASV-30 reduced anxiety-like behavior inBALB/c mice in three models of anxiety: marble burying [minimaleffective dose (MED) = 3 nmol], open field (MED = 3 nmol), andelevated plus maze (MED = 0.1 nmol). ASV-30 did not change locomotoractivity or the adrenocorticotropic hormone (ACTH) response torestraint stress. The potent mixed CRF₁/CRF₂ antagonist astressinnot only reduced anxiety-like behavior in all three models withequivalent potency but also blunted the ACTH response to restraintstress. Finally, the new selective CRF₂ receptor agonist urocortin-IIproduced a dose-dependent increase in anxiety-like behavior inthe plus maze test. Therefore, our data suggest that the CRF₂receptor plays a role in the behavioral, but not the hypothalamic-pituitary-adrenalaxis, response tostress.

¹ Present address: Department of Metabolic Research, Bristol-Meyers Squibb, 311 Pennington-Rocky Hill Rd., Pennington, NJ08543.

0022-3565/02/3021-0145$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics

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