Human Urocortin II, a Selective Agonist for the Type 2 Corticotropin-Releasing Factor Receptor, Decreases Feeding and Drinking in the Rat

Abstract

Corticotropin-releasing factor (CRF) has been hypothesized to modulate consummatory behavior through the Type 2 CRF (CRF 2 ) receptor. However, behavioral functions subserved by the CRF 2 receptor remain poorly understood. Recently, human urocortin II (hUcn II), a selective CRF 2 receptor agonist, was identified. To study the effects of this neuropeptide on ingestive behavior, we examined the effects of centrally infused hUcn II (i.c.v. 0, 0.01, 0.1, 1.0, 10.0 g) on the microstructure of nosepoke responding for food and water in nondeprived, male rats. Malaise-inducing properties of the peptide were monitored using conditioned taste aversion (CTA) testing. To identify potential sites of action, central induction of Fos protein expression was examined. hUcn II dose dependently reduced the quantity and duration of responding for food and water at doses lower (0.01-1.0 g) than that forming a CTA (10 g). Effects were most evident during hours 4 to 6 of the dark cycle. Meal pattern analysis showed that hUcn II potently (0.1 g) increased the satiating value of food. Rats ate and drank smaller and shorter meals without changing meal frequency. Rats also ate more slowly. hUcn II induced Fos in regions involved in visceral sensory processing and autonomic/neuroendocrine regulation and resembling those activated by appetite suppressants. hUcn II is a promising neuropeptide for investigating the role of the CRF 2 receptor in ingestive behavior.Corticotropin-releasing factor (CRF) is hypothesized to mediate behavioral, autonomic, endocrine, and immunological responses to stress (Koob and Heinrichs, 1999). Intracerebroventricular (i.c.v.) administration of CRF in rats mimics several behavioral effects of stress, including motor activation, anxiety-like behavior, anorexia, reduced sexual behavior, and altered cognitive performance (Koob et al., 1994). Two genes encoding separate families of G-protein coupled CRF receptors, each having distinct distributions and functional and pharmacological properties (Perrin and Vale, 1999), have been identified (CRF 1 and CRF 2 ). Whereas molecular and receptor antagonist studies point to activating and anxiogenic-like roles of the CRF 1 receptor (Koob and Heinrichs, 1999), behavioral functions mediated by the CRF 2 receptor have remained obscure.

Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval

“…Unlike LiCl, the minimal effective dose for Ucn 3 anorexia (i.c.v. 1 mg) did not promote formation of a CTA, although, similar to Ucn 2 (Inoue et al, 2003), significantly higher doses might. A caveat to this conclusion is that Ucn 3's anorectic effects are delayed, and the formation of a CTA depends on temporal proximity between the conditioned stimulus and the aversive drug state, so it would be useful to evaluate Ucn 3's actions in a time-insensitive measure of malaise.…”

“…In this vein, the related CRF 2 agonist Ucn 2 did not increase kaolin clay intake (pica), an unconditioned measure of visceral illness at doses through 10 mg (Zorrilla et al, 2004). Still, it cannot be ruled out that aversive, 'non-visceral' actions of high doses of Ucn 2 (Inoue et al, 2003) that promoted a CTA might be shared by high doses of Ucn 3. Arguing against anxiogenic-like actions, i.c.v.…”

“…To determine whether anorectic doses of LV Ucn 3 produced a malaise-like state, individually housed rats (n ¼ 21) were tested in a sensitive, 12-day, multiple-pairing, two-bottle choice conditioned taste aversion (CTA) procedure as described previously (Inoue et al, 2003). Briefly, rats were accustomed for 1 week to acquire their total daily fluid intake during brief, defined periods by providing rats limited (25-min) home cage access to two sipper tube bottles, each containing tap water beginning at 0930 h. On days 8 and 10 (preconditioning and post-conditioning 1), rats had limited access to one bottle with a 7.31 mM Na saccharin solution (0.15% w/v; Sigma, St Louis, MO, USA) and one bottle with tap water.…”

“…As a positive control, separate rats (n ¼ 14) were administered isotonic (0.15 M) LiCl (Sigma) or NaCl intraperitoneally (20 ml/kg) postsaccharin access instead of Ucn 3. This dose of LiCl is known to induce taste aversion via gastrointestinal discomfort (Seeley et al, 2000;Inoue et al, 2003). A relative decrease in saccharin preference ratio is interpreted as the formation of a conditioned taste aversion.…”

“…We and others found that i.c.v. Ucn 2 reduced nocturnal food intake (Zorrilla et al, 2004), beginning 3-6 h postinjection in nondeprived rats (Inoue et al, 2003;Ohata and Shibasaki, 2004;de Groote et al, 2005) or mice (Reyes et al, 2001). Ucn 3 (i.c.v.)…”