Abstract

Corticotropin-releasing factor (CRF) is one of the principle components of the stress response. The physiological effects of CRF are mediated by two receptor subtypes, CRF₁ and CRF₂. Recent data obtained with the selective CRF₂ antagonist antisauvagine-30 (ASV-30) has begun to suggest that both CRF receptor subtypes may play a role in stress-related behaviors. Exactly how these two receptor subtypes interact to modulate the behavioral and endocrine responses to stress is not clear, however. We have attempted to understand the role of the CRF₂ receptor in the behavioral and endocrine responses to stress by comparing the effects of ASV-30 with the mixed CRF₁/CRF₂ receptor antagonist astressin. Centrally administered ASV-30 reduced anxiety-like behavior in BALB/c mice in three models of anxiety: marble burying [minimal effective dose (MED) = 3 nmol], open field (MED = 3 nmol), and elevated plus maze (MED = 0.1 nmol). ASV-30 did not change locomotor activity or the adrenocorticotropic hormone (ACTH) response to restraint stress. The potent mixed CRF₁/CRF₂antagonist astressin not only reduced anxiety-like behavior in all three models with equivalent potency but also blunted the ACTH response to restraint stress. Finally, the new selective CRF₂receptor agonist urocortin-II produced a dose-dependent increase in anxiety-like behavior in the plus maze test. Therefore, our data suggest that the CRF₂ receptor plays a role in the behavioral, but not the hypothalamic-pituitary-adrenal axis, response to stress.