PEGylated cholecystokinin is more potent in inducing anorexia than conditioned taste aversion in rats

Background and purpose: The physiological involvement of endogenous cholecystokinin (CCK) in the termination of feeding has been challenged by evidence of aversive effects of exogenous CCK ₈. We previously prolonged the anorectic effect of CCK by conjugation to polyethylene glycol (PEGylation) to produce PEG-CCK ₉. In this study, we investigated the ability of different doses of PEG-CCK ₉ to induce conditioned taste aversion (CTA) and satiety and identified the receptors involved in CTA induction. Experimental approach: Induction of CTA, measured by the saccharin preference ratio determined in a two-bottle CTA procedure, and of satiety in adult male Wistar rats after intraperitoneal (i.p.) injection of different doses of PEG-CCK ₉ (1, 2, 4, 8, 16 or 32 μg kg ^-1) was compared. Devazepide (100 μg kg ^-1) and 2-NAP (3 mg kg ^-1), two selective CCK ₁-receptor antagonists, were co-administered i.p. with PEG-CCK ₉ (8 μg kg ^-1) and the CTA effects monitored. Key results: PEG-CCK ₉ dose-dependently induced CTA, with a minimal effective dose of 8 μg kg ^-1, whereas the minimal effective dose to induce satiety was 1 μg kg ^-1. The CTA effects of PEG-CCK ₉ were completely abolished by i.p. administration of devazepide prior to PEG-CCK ₉ treatment and only partially abolished by administration of 2-NAP. Conclusions and implications: Although PEG-CCK ₉-induced satiety and PEG-CCK ₉-induced CTA both increased with dose, the conjugate was more potent in inducing satiety, suggesting that the anorexia could not be completely attributed to the aversiveness of the drug. As observed with induction of satiety, PEG-CCK ₉-induced CTA was mediated by CCK ₁-receptors.