Abstract

The corticotropin-releasing factor (CRF) system mediates stress responses. Extrahypothalamic CRF₁ receptor activation has anxiogenic-like properties, but anxiety-related functions of CRF₂ receptors remain unclear. The present study determined the effects of intracerebroventricular administration of a CRF₂ agonist, urocortin 3, on behavior of male Wistar rats in the shock-probe, social interaction, and defensive withdrawal tests of anxiety-like behavior. Equimolar doses of stressin₁-A, a novel CRF₁ agonist, were administered to separate rats. The effects of pyrazolo[1,5-a]-1,3,5-triazin-4-amine,8-[4-(bromo)-2-chlorophenyl]-N, N-bis(2-methoxyethyl)-2,7-dimethyl-(9Cl) (MJL-1-109-2), a CRF₁ antagonist, on behavior in the shock-probe test also were studied. Stressin₁-A increased anxiety-like behavior in the social interaction and shock-probe tests. Stressin₁-A elicited behavioral activation and defensive burying at lower doses (0.04 nmol), but it increased freezing, grooming, and mounting at 25-fold higher (1-nmol) doses. Conversely, systemic administration of MJL-1-109-2 (10 mg/kg) had anxiolytic-like effects in the shock-probe test. Unlike stressin₁-A or MJL-1-109-2, i.c.v. urocortin 3 infusion did not alter anxiety-like behavior in the shock-probe test across a range of doses that reduced locomotion and rearing and increased grooming. Urocortin 3 also did not decrease social interaction, but it decreased anxiety-like behavior in the defensive withdrawal test at a 2-nmol dose. Thus, i.c.v. administration of CRF₁ and CRF₂ agonists produced differential, but not opposite, effects on anxiety-like behavior. Urocortin 3 (i.c.v.) did not consistently decrease or increase anxiety-like behavior, the latter unlike effects seen previously after local microinjection of CRF₂ agonists into the septum or raphe. With increasing CRF₁ activation, however, the behavioral expression of anxiety qualitatively changes from “coping” to “noncoping” and offensive, agonistic behaviors.