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REGULATION IN GENETICALLY MODIFIED ANIMALS

c-Kit mutant mouse behavioral phenotype: altered meal patterns and CCK sensitivity but normal daily food intake and body weight

Laboratory of Regulatory Psychobiology, Department of Psychological Sciences, Purdue University, West Lafayette, Indiana 47097

Submitted 10 January 2003 ; accepted in final form 12 June 2003

The mouse W/W^v mutation of the c-Kit receptor causes extensive loss of gastrointestinal interstitial cells of Cajal and vagal intramuscular arrays (IMAs; one of the two putative mechanoreceptors in gastrointestinal smooth muscle). To characterize the behavioral phenotype of the c-Kit mouse and to evaluate the roles of these mechanoreceptors in controlling food intake, meal patterns and daily intakes of W/W^v mice and controls were examined using solid (20-mg pellets) and liquid (Isocal) maintenance diets. After the meal pattern experiments, CCK (0.5, 1, 2, 4, 8, and 16 µg/kg ip) was administered to examine the role of the interstitial cells and vagal IMA mechanoreceptors in relaying peripheral signals of satiety activated by CCK-A receptors, whereas the specificity of the response was assessed with the antagonist devazepide (300 µg/kg ip). On both diets, the W/W^v mice ate smaller meals for shorter durations, with a compensatory increase in meal number, resulting in daily intakes and body weights similar to the controls. After CCK injections, the mutant mice consistently suppressed intake more (2x) in 30-min tests, regardless of the test diet (12.5% glucose, chow, pellets, and Isocal). The increased sensitivity of W/W^v mice to CCK reflected an increased potency of the hormone (c-Kit mouse ED₅₀ = 2.4 µg/kg; control ED₅₀ = 6.4 µg/kg) and a shift of the dose-response curve to the left. Devazepide blocked the CCK suppression of ingestion. These results indicate that the selective loss of the interstitial cells and IMAs disrupts short-term feeding of the W/W^v mice by inducing an earlier satiety, possibly by altering gastric accommodation and/or emptying, without affecting the long-term mechanisms controlling overall intake or body weight. The results also suggest that the reduction of interstitial cells and IMAs augments the sensitivity to or increases the efficiency of exogenous CCK.

feeding; devazepide; microstructure; intramuscular arrays; interstitial cells of Cajal

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