Human Urocortin 2, a Corticotropin-Releasing Factor (CRF) 2 Agonist, and Ovine CRF, a CRF 1 Agonist, Differentially Alter Feeding and Motor Activity Eric P. Zorrilla, Lindsay E. Reinhardt, Glenn R. Valdez, Koki Inoue, Jean E. Rivier, Wylie W. Vale, and George F. Koob Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California (E.P.Z., L.E.R., G.R.V., K.I., G.F.K.); Department of Neuropsychiatry, Osaka City University Medical School, Osaka, Japan (K.I.); and Peptide Biology Laboratory, The Salk Institute for Biological Sciences, La Jolla, California (J.E.R., W.W.V.) Received March 18, 2004; accepted April 28, 2004 ABSTRACT Two corticotropin-releasing factor (CRF) receptor families have been identified (CRF 1 and CRF 2 ). Whereas anxiogenic-like roles for the CRF 1 receptor have been identified, behavioral functions of the CRF 2 receptor remain obscure. Urocortin 2 (Ucn 2), a CRF-related peptide that selectively binds CRF 2 receptors, was recently identified and recognized for its central anorectic prop- erties. The present study tested the hypothesis that the anorex- igenic mode of action of Ucn 2 differed from that of ovine CRF (oCRF), a preferential CRF 1 receptor agonist. The behavioral effects of intracerebroventricular administration of Ucn 2 were compared with those of oCRF in nondeprived male Wistar rats (n = 102). Ucn 2 reduced 6-h food and water intake at doses that did not induce visceral illness (0.1, 1, and 10 g), as indicated by kaolin intake. Ucn 2 retained its potent anorectic activity in rats receiving a highly palatable cafeteria diet, pref- erentially reducing intake of carbohydrate (CHO)-rich items while sparing intake of mixed-fat/CHO items. In contrast to Ucn 2, oCRF (10 g) suppressed 6-h intake of cafeteria diet-fed rats without regard to macronutrient composition. Rather, oCRF most potently suppressed intake of preferred food items. Whereas oCRF had short-onset motor-activating effects, Ucn 2 had nondose-dependent, delayed-onset motor-suppressing effects. Thus, central infusion of a CRF 2 receptor agonist sup- pressed intake of both bland and palatable diets without induc- ing behavioral arousal or malaise, and the profile of anorexi- genic effects qualitatively differed from those of a CRF 1 receptor agonist. The results suggest the existence of distinct forms of CRF 1 - and CRF 2 -mediated anorexia. The neuropeptide corticotropin-releasing factor (CRF) (Vale et al., 1981) is hypothesized to mediate behavioral, autonomic, and endocrine responses to stress (Zorrilla and Koob, 2004a). Two genes code for separate families of G- protein-coupled CRF receptors (CRF 1 and CRF 2 ) with dis- tinct distributions and pharmacological properties (Zorrilla and Koob, 2004a). Molecular and antagonist studies point to arousing and anxiogenic-like roles for the CRF 1 receptor (Zorrilla and Koob, 2004b), but behavioral functions of the CRF 2 receptor remain obscure. The characterization of urocortin 1 (Ucn 1) (Vaughan et al., 1995), a mammalian CRF paralog with greater affinity for the CRF 2 receptor than CRF, led to two hypotheses about the behavioral significance of the CRF 2 receptor. First, because i.c.v. Ucn 1 had more potent, efficacious, and prolonged an- orectic effects than CRF (Spina et al., 1996), it was hypoth- esized that CRF 2 receptor activation suppressed feeding. Studies with a preferential CRF 2 receptor antagonist and CRF 2 receptor-deficient mice supported this hypothesis (Zor- rilla et al., 2003). Second, because i.c.v. Ucn 1 was less effective than CRF in stimulating motor activity in a familiar environment (Spina et al., 1996; Reyes et al., 2001), it was hypothesized that CRF 2 receptor activation had motor sup- pressive effects. Selective agonists for the CRF 2 receptor had not been identified, however, precluding determination of whether CRF 2 receptor activation was sufficient for these effects. Genes encoding two selective CRF 2 agonists— urocortin 2 (Ucn 2) and urocortin 3 (Ucn 3)—were recently cloned from This study was supported by Grants DK26741 and DK64871 from the National Institute of Diabetes and Digestive and Kidney Diseases. G.R.V. was supported by AA05563, an Individual National Research Service Award from the National Institute on Alcohol Abuse and Alcoholism, and is now at the New England Primate Research Center, Harvard Medical School (Southborough, MA). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.104.068676. ABBREVIATIONS: CRF, corticotropin-releasing factor; Ucn 1, urocortin 1; Ucn 2, urocortin 2; Ucn 3, urocortin 3; oCRF, ovine CRF; CTA, conditioned taste aversion; hUcn 2, human Ucn 2; CHO, carbohydrate; MED, minimum effective dose. 0022-3565/04/3103-1027–1034$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 310, No. 3 Copyright © 2004 by The American Society for Pharmacology and Experimental Therapeutics 68676/1163115 JPET 310:1027–1034, 2004 Printed in U.S.A. 1027 at ASPET Journals on July 20, 2018 jpet.aspetjournals.org Downloaded from