Attenuated satiation response to intestinal nutrients in rats that do not express CCK-A receptors Mihai Covasa a, *, Robert C. Ritter b a Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, Washington 99164, USA b Program in Neuroscience, Washington State University, Pullman, Washington 99164, USA Received 3 January 2001; accepted 17 January 2001 Abstract Pharmacological experiments suggest that satiation associated with intestinal infusion of several nutrients is mediated by CCK-A receptors. Otsuka Long-Evans Tokushima Fatty, (OLETF), rats do not express CCK-A receptors and are insensitive to the satiation- producing effects of exogenous CCK. To further evaluate the role of CCK-A receptors in satiation by intestinal nutrient infusion, we examined intake of solid (pelleted rat chow) or liquid (12.5% glucose) food intake, following intestinal infusions of fats (oleic acid or fat emulsion), sugars (maltotriose or glucose), or peptone in OLETF rats and Long Evans Tokushima Otsuka control rats (LETO). Intestinal infusion of glucose or maltotriose reduced solid food intake more in LETO than in OLETF rats from 30 min through 4 h post infusion. Reduction of solid food intake by intestinal infusions of fat or peptone did not differ between OLETF and LETO rats during the first 30 min post infusion, but reduction of intake by these infusates was attenuated in OLETF rats over the ensuing 4h post infusion. Intestinal infusion of glucose, oleate, fat emulsion and peptone reduced 30-min intake of 12.5% glucose more in LETO than OLETF rats. Furthermore, pretreatment with the CCK-A receptor antagonist, devazepide, attenuated intestinal nutrient-induced reduction of food intake only in LETO, but not OLETF rats. Our results confirm pharmacological results, indicating that CCK-A receptors participate in satiation by nutrients that elevate plasma CCK concentrations, as well as by nutrients that do not stimulate secretion of endocrine CCK. In addition, our results indicate: 1) that OLETF rats have deficits in the satiation response to a variety of intestinal nutrient infusions; 2) that the temporal pattern for CCK-A receptor participation in satiation by intestinal nutrients is different during ingestion of liquid and solid foods and 3) that intestinal nutrients provide some satiation signals that are CCK-A receptor mediated and some that are not. © 2001 Elsevier Science Inc. All rights reserved. Keywords: Food intake; Satiation; Obesity; Nutrient infusion; OLETF; CCK 1. Introduction Infusions of nutrients into the upper small intestine re- sults in reduced food intake via activation of small unmy- elinated vagal sensory neurons [see [25], for review]. Re- duction of food intake by intraintestinal nutrient infusions is thought to exercise controls of food intake, which normally are activated when components of a meal enter the duode- num from the stomach. Some, but not all, intestinal nutri- ents stimulate secretion of the gut peptide, cholecystokinin (CCK). CCK reduces food intake by acting at CCK-A receptors, located on small unmyelinated vagal sensory neu- rons [14,16], indicating that the substrate that mediates CCK-induced satiation is similar, if not identical, to that which mediates reduction of food intake by intestinal nutri- ents. Participation of CCK-A receptors in reduction of food intake by intestinal nutrients is well supported by the fact that CCK-A receptor antagonists attenuate or abolish reduc- tion of food intake by intraintestinally infused triglycerides [9], long chain fatty acids [4,32,37], oligosaccharides [2,31] and protein [33]. In addition to reversing the reduction of food intake observed following exogenous CCK [3,16,19] injection or intestinal nutrient infusion, CCK-A receptor antagonists increase food intake when they are administered alone [1,19,23,24,28]. Taken together, these results suggest a direct relationship between CCK-A receptors and control of food intake by intestinal nutrients. Recently, the Otsuka Long-Evans Tokushima fatty rat (OLETF), which has a mutation that prevents expression of the CCK-A receptor has been described [7,8]. These ani- * Corresponding author. Tel.: +1-509-335-7675; fax: +1-509-335- 4650. E-mail address: Mcovasa@vetmed.wsu.edu (M. Covasa). Peptides 22 (2001) 1339 –1348 0196-9781/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S0196-9781(01)00461-2