PEGylated cholecystokinin prolongs satiation in rats: dose dependency and receptor involvement

Background and purpose: Acute intraperitoneal (i.p.) administration of cholecystokinin (CCK) is known to induce a significant, but short‐lasting, reduction in food intake, followed by recovery within hours. Therefore, we had covalently coupled CCK to a 10 kDa polyethylene glycol and showed that this conjugate, PEG‐CCK 9 , produced a significantly longer anorectic effect than unmodified CCK 9 . The present study assessed the dose–dependency of this response and the effect of two selective CCK 1 receptor antagonists, with different abilities to cross the blood‐brain barrier (BBB), on PEG‐CCK 9 ‐induced anorexia. Experimental approach: Food intake was measured, for up to 23 h, after i.p. administration of different doses (2, 4, 8, 16 and 32 μ g kg −1 ) of CCK 9 or PEG‐CCK 9 in male Wistar rats. Devazepide (100 μ g kg −1 ), which penetrates the BBB or 2‐NAP (3 mg kg −1 ), which does not cross the BBB, were coadministered i.p. with PEG‐CCK 9 (6 μ g kg −1 ) and food intake was monitored. Key results: In PEG‐CCK 9 ‐treated rats, a clear dose‐dependency was seen for both the duration and initial intensity of the anorexia whereas, for CCK 9 , only the initial intensity was dose‐dependent. Intraperitoneal administration of devazepide or 2‐NAP, injected immediately prior to PEG‐CCK 9 , completely abolished the anorectic effect of PEG‐CCK 9 . Conclusions and implications: The duration of the anorexia for PEG‐CCK 9 was dose‐dependent, suggesting that PEGylation of CCK 9 increases its circulation time. Both devazepide and 2‐NAP completely abolished the anorectic effect of i.p. PEG‐CCK 9 indicating that its anorectic effect was solely due to stimulation of peripheral CCK 1 receptors. British Journal of Pharmacology (2007) 152 , 396–403; doi: 10.1038/sj.bjp.0707390 ; published online 9 July 2007