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

Abstract

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 mg kg À1 ) was compared. Devazepide (100 mg kg À1 ) and 2-NAP (3 mg kg À1 ), two selective CCK 1 -receptor antagonists, were co-administered i.p. with PEG-CCK 9 (8 mg kg À1 ) and the CTA effects monitored. Key results: PEG-CCK 9 dose-dependently induced CTA, with a minimal effective dose of 8 mg kg À1 , whereas the minimal effective dose to induce satiety was 1 mg kg À1 . 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.

Metabolic effects of activation of CCK receptor signaling pathways by twice-daily administration of the enzyme-resistant CCK-8 analog, (pGlu-Gln)-CCK-8, in normal mice

“…In agreement, circulating glucose and insulin were almost identical to saline-treated control mice, indicating lack of detrimental metabolic effects despite significantly lowered body weights. These observations accord with other studies using longer-acting CCK agonists, where the occurrence of adverse effects such as intestinal discomfort, tolerance, and conditioned taste aversion was atypical and dose related (Verbaeys et al 2008(Verbaeys et al , 2009a. The finding in one study of pancreatic hyperplasia and, in some cases, pancreatitis in rats treated with a long-acting PEGylated version of CCK-9 for 14 days (Verbaeys et al 2009a) was not replicated in previous investigations with (pGlu-Gln)-CCK-8, where amylase and lipase levels were actually reduced (Irwin et al 2012).…”

Lack of tolerance development with long-term administration of PEGylated cholecystokinin

“…We therefore previously investigated the ability of PEG-CCK 9 to induce a conditioned taste aversion (CTA). We demonstrated that PEG-CCK 9 induces both satiety and CTA and that both effects increase with dose [37]. A dose of 8 mg kg À1 was the minimal effective dose to produce CTA.…”

“…A dose of 8 mg kg À1 was the minimal effective dose to produce CTA. However, even at this dose, the PEGylated conjugate is more potent in inducing satiety, suggesting that the anorexia cannot be completely attributed to the aversiveness of the drug [37]. Experiments using smaller doses of PEG-CCK 9 and thus inducing a lesser degree of aversiveness, might be useful to unravel the contribution of the PEG-CCK 9 -induced CTA in the observed lack of tolerance.…”

Calcitonin Receptor Neurons in the Mouse Nucleus Tractus Solitarius Control Energy Balance via the Non-aversive Suppression of Feeding

“…tractus solitarius (NTS; a CNS region crucial for integrating gutderived prandial signals and promoting meal termination) (Beutler et al, 2017;Blouet and Schwartz, 2012;D'Agostino et al, 2016;Hayes, 2009, 2012;Hayes et al, 2011Hayes et al, , 2016aHayes et al, 2010Hayes et al, , 2016b) also contains Calcr cells (Calcr NTS neurons). Importantly, while agonists for CALCR (and other gut peptide receptors) decrease food intake, they also produce aversive responses that mimic gut malaise (Adams et al, 2018;Halatchev and Cone, 2005;Schier et al, 2012;Verbaeys et al, 2008), potentially limiting their therapeutic utility.…”