RAPID DEVELOPMENT OF TOLERANCE TO THE BEHAVIORAL ACTIONS OF CHOLECYSTOKININ
RAPID DEVELOPMENT OF TOLERANCE TO THE BEHAVIORAL ACTIONS OF CHOLECYSTOKININ
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DOI：
10.1038/302703a0
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发表时间：
1983-01-01
期刊：
影响因子：
64.8
通讯作者：
BEINFELD, MC
中科院分区：
文献类型：
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作者：
CRAWLEY, JN;BEINFELD, MC
胆囊收缩素（CCK）对禁食大鼠1 -4、小鼠5 -7、绵羊8、猪9、猴10和人11 -13的摄食量有急性抑制作用。CCK被认为是一种饱腹感信号，诱导饱腹感的行为序列2，或作为一种令人厌恶的内部刺激，通过诱导不适来抑制食物摄入4。食物摄入量和相关探索行为的减少是由CCK在其肠道外周受体启动的，其似乎通过迷走神经将感觉反馈传递到介导食欲行为的大脑区域15 -17。CCK作为食欲抑制剂在肥胖综合征中的治疗潜力取决于显着，持久的体重减轻的证明。由于CCK肽在体内迅速降解，因此通过重复注射长期给予CCK存在问题。我们选择Alzet恒定输注渗透微型泵，以研究持续输注CCK期间体重和摄食量的可能变化。我们现在报告，在腹膜内（i. p.）输注CCK。缺乏慢性CCK效应的机制似乎是行为耐受性的快速发展。急性激发剂量的CCK诱导饱腹相关行为的生理盐水输注大鼠在CCK输注大鼠无效。在植入微型泵后的几个小时内，行为耐受是明显的。这些结果提供了第一个证据，表明快速和可逆的耐受性发展到一个肠肽的行动。
Cholecystokinin (CCK) acts acutely to inhibit food consumption in fasted rats1–4, mice5–7, sheep8, pigs9, monkeys10and humans11–13. CCK has been proposed as a satiety signal, inducing the behavioural sequence of satiety2, or as an aversive internal stimulus, which inhibits food intake by inducing malaise4. Reductions in food intake and related exploratory behaviours are initiated by CCK at its peripheral receptor in the gut, which appears to transmit sensory feedback via the vagus nerve to brain regions mediating appetitive behaviours15–17. The therapeutic potential of CCK as an appetite suppressant in obesity syndromes rests on the demonstration of significant, long-lasting body weight reduction. Chronic CCK administration by repeated injections is problematic, since this peptide is rapidly degradedin vivo. We chose the Alzet constant infusion osmotic minipump to investigate possible alterations in body weight and food intake during continuous infusion of CCK. We now report that no change was detected in either body weight or total daily food consumption at any time point during 2 weeks of intraperitoneally (i.p.) infused CCK. The mechanism underlying the lack of chronic CCK effects appears to be a rapid development of behavioural tolerance. Acute challenge doses of CCK which induced satiety-related behaviours in saline-infused rats were ineffective in CCK-infused rats. The behavioural tolerance was apparent within a few hours of minipump implantation. These results provide the first evidence that rapid and reversible tolerance develops to the actions of a gut peptide.