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.
Footnotes
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This work was supported by National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism Grant AA006420 (to F.W.), National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Grants 26741 (to E.P.Z., J.E.R., and W.W.V.) and 64871 (to E.P.Z.), and partially supported by the Clayton Medical Research Foundation, Inc. (to W.W.V.). It also was supported in part by funds from the Intramural Research Program/National Institutes of Health, the National Institute on Drug Abuse, and the National Institute of Diabetes and Digestive and Kidney Diseases (to K.C.R.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.123208.
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ABBREVIATIONS: CRF, corticotropin-releasing factor; Ucn, urocortin; BP, binding protein; m, mouse; o, ovine; MJL-1-109-2, pyrazolo[1,5-a]-1,3,5-triazin-4-amine,8-[4-(bromo)-2-chlorophenyl]-N, N-bis(2-methoxyethyl)-2,7-dimethyl-(9Cl); ANOVA, analysis of variance; DMP696, 4-(1,3-dimethoxyprop-2-ylamine)-2,7-dimethyl-8-(2,4-dichlorophenyl)-pyrazolo[1,5-α]-1,3,5-triazine; SSR125543A, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl) ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received March 21, 2007.
- Accepted September 6, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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