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, CRF 1 and CRF 2 . Recent data obtained with the selective CRF 2 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 CRF 2 receptor in the behavioral and endocrine responses to stress by comparing the effects of ASV-30 with the mixed CRF 1 /CRF 2 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) ϭ 3 nmol], open field (MED ϭ 3 nmol), and elevated plus maze (MED ϭ 0.1 nmol). ASV-30 did not change locomotor activity or the adrenocorticotropic hormone (ACTH) response to restraint stress. The potent mixed CRF 1 /CRF 2 antagonist 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 CRF 2 receptor agonist urocortin-II produced a dose-dependent increase in anxiety-like behavior in the plus maze test. Therefore, our data suggest that the CRF 2 receptor plays a role in the behavioral, but not the hypothalamic-pituitary-adrenal axis, response to stress.Most anxiety disorders are characterized by the physiological symptoms of arousal, including increased heart rate, blood pressure, and plasma catecholamines (U.S. Department of Health and Human Services, 1999). Central CRF administration mimics many of the above-mentioned symptoms (for review, see Dunn and Berridge, 1990) and produces stress-like behavioral responses such as immobility or activation, depending upon the familiarity of the environment (Britton et al., 1982(Britton et al., , 1986. In addition, CRF antagonists attenuate stress-like behaviors in anxiety-inducing paradigms such as the plus maze task, defensive withdrawal, conditioned fear, and open field, suggesting that CRF may play a physiological role in behaviors induced by stressful situations (Britton et al., 1986;Kalin et al., 1988;Menzaghi et al., 1994;Deak et al., 1999;Okuyama et al., 1999;Arborelius et al., 2000). Finally, CRF is elevated in the cerebrospinal fluid of anxiety patients (De Souza and Nemeroff, 1990), suggesting that the CRF system may be hyperactive in anxiety disorders.The physiological effects of CRF are mediated by two receptor subtypes, CRF 1 and CRF 2 (Grigoriadis et al., 1996). Although all of the CRF-related peptides bind with similar affinity to the CRF 1 receptor, CRF itself is about 30-fold less potent at the CRF 2 receptor than urocortin, urotensin, and sauvagine (Donaldson et al., 1996) and greater than 100-fold less potent at the CRF 2 receptor than the recently discovered urocortin II (Reyes et al....
