Fink H, Rex A, Voits M, Voigt J P
Institute of Pharmacology and Toxicology, Medical Faculty, Charité, Humboldt University at Berlin, Germany.
Exp Brain Res. 1998 Nov;123(1-2):77-83. doi: 10.1007/s002210050546.
Cholecystokinin (CCK) is one of the first discovered gastrointestinal hormones and one of the most abundant neuropeptides in the brain. Two types of CCK receptors have been identified: (1) CCK-A receptors are mainly located in the periphery, but are also found in some areas of the CNS; and (2) CCK-B receptors are widely distributed in the brain. Major biological actions of CCK are the reduction of food intake and the induction of anxiety-related behavior. Inhibition of feeding is mainly mediated by the A-type receptors, whereas anxiety-like behavior is induced by stimulating B-type receptors. This paper presents new findings on the effects of the biologically active CCK agonists, CCK-8S, CCK-4, and A71378. The results reviewed suggest that the hypophagic effects of CCK are strongly dependent on the experimental design, sex, and age of the rats. For example, food intake measured during the night or after food deprivation is reduced by CCK-8S in young adult and aged rats, whereas, under fixed feeding conditions, CCK-8S does not inhibit food intake in young adult rats. The sensitivity to the hypophagic CCK effect increases with age in male and female rats; however, female rats are less sensitive to the CCK action. Further, using a nongenetic and non-stressful model of obesity due to unspecific postnatal overfeeding, the satiating effect of moderate CCK-8S doses is weaker in obese than in normal rats. Again, the hypophagic effect is more pronounced in male than in female obese and normal rats. Considering that aversive reactions in rats are markedly influenced by strain and breeding-line variations, research results in this area are critically reviewed. It is shown that anxiety-like symptoms can only be induced by a selectively acting CCK-B agonist, whereas mixed CCK-A and -B agonists and selective CCK-A agonists fail to change behavior in anxiety tests. CCK-4 induces stable and reproducible anxiogenic-like behavior only in certain rat strains. Moreover, CCK-4 effects can be demonstrated in the conflict test, in the ultrasonic vocalization test in rat pups, on the elevated plus maze, and in the black and white box, but not in the social interaction test. CCK has also been reported to modulate memory processes. On the one hand, CCK-8S and CCK-4 enhanced habituation to the novelty of a hole board. On the other hand, repeated administration of CCK-8S did not improve maze performance in aged rats. The literature on the behavioral pharmacology of CCK is rife with inconsistency and contradiction. The major biological actions of CCK depend on the receptor selectivity of the CCK fragments used and on organismic and procedural variables. All these variables potentially influence behavioral responses in rats. Therefore, in CCK research more attention should be paid to the importance of these methodological factors.
胆囊收缩素（CCK）是最早发现的胃肠激素之一，也是大脑中含量最丰富的神经肽之一。已鉴定出两种类型的CCK受体：（1）CCK-A受体主要位于外周，但也存在于中枢神经系统的某些区域；（2）CCK-B受体广泛分布于大脑中。CCK的主要生物学作用是减少食物摄入和诱发焦虑相关行为。摄食抑制主要由A型受体介导，而焦虑样行为则由刺激B型受体诱发。本文介绍了生物活性CCK激动剂CCK-8S、CCK-4和A71378作用的新发现。综述结果表明，CCK的促食欲减退作用强烈依赖于实验设计、大鼠的性别和年龄。例如，CCK-8S可降低年轻成年大鼠和老年大鼠夜间或禁食后的食物摄入量，而在固定喂养条件下，CCK-8S不会抑制年轻成年大鼠的食物摄入。雄性和雌性大鼠对CCK促食欲减退作用的敏感性随年龄增加而增加；然而，雌性大鼠对CCK作用的敏感性较低。此外，使用非特异性产后过度喂养导致的非遗传和非应激性肥胖模型，中等剂量CCK-8S的饱腹感作用在肥胖大鼠中比正常大鼠弱。同样，促食欲减退作用在雄性肥胖和正常大鼠中比雌性更明显。考虑到大鼠的厌恶反应受品系和繁殖系变异的显著影响，对该领域的研究结果进行了批判性综述。结果表明，只有选择性作用的CCK-B激动剂才能诱发焦虑样症状，而CCK-A和-B混合激动剂以及选择性CCK-A激动剂在焦虑测试中不能改变行为。CCK-4仅在某些大鼠品系中诱导稳定且可重复的焦虑样行为。此外，CCK-4的作用可在冲突测试、幼鼠超声发声测试、高架十字迷宫和黑白箱测试中得到证实，但在社交互动测试中则不然。据报道，CCK还可调节记忆过程。一方面，CCK-8S和CCK-4增强了对孔板新奇性的习惯化。另一方面，重复给予CCK-8S并不能改善老年大鼠的迷宫表现。关于CCK行为药理学的文献充满了不一致和矛盾之处。CCK的主要生物学作用取决于所用CCK片段的受体选择性以及机体和实验程序变量。所有这些变量都可能影响大鼠的行为反应。因此，在CCK研究中，应更加关注这些方法学因素的重要性。
