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BEHAVIORAL PHARMACOLOGY

Subtype-Selective Corticotropin-Releasing Factor Receptor Agonists Exert Contrasting, but Not Opposite, Effects on Anxiety-Related Behavior in Rats

Committee on the Neurobiology of Addictive Disorders (Y.Z., E.M.F., E.P.Z.), Harold L. Dorris Neurological Research Institute (Y.Z., E.M.F., E.P.Z.), and Molecular and Integrative Neurosciences Department (Y.Z., F.W.), The Scripps Research Institute, La Jolla, California; Department of Psychology, Grand Valley State University, Allendale, Michigan (G.R.V.); Institute of Physiology, Pécs University Medical School, Pécs, Hungary (É.M.F.); Peptide Biology Laboratory, Salk Institute, La Jolla, California (J.E.R., W.W.V.); and Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland (K.C.R.)

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.

Address correspondence to: Dr. Eric P. Zorrilla, Committee on the Neurobiology of Addictive Disorders, SP30-2400, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. E-mail: ezorrilla{at}scripps.edu

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