Chiodo L A, Freeman A S, Bunney B S
Brain Res. 1987 May 5;410(2):205-11. doi: 10.1016/0006-8993(87)90317-9.
Recent evidence suggests that the glutaramic acid derivative proglumide (PROG) is a selective antagonist of cholecystokinin (CCK) in the rat CNS. The extent of this selectivity has now been characterized in more detail. Iontophoretic or intravenous (i.v.) administration of PROG was ineffective against the excitatory effect of iontophoretically applied neurotensin on midbrain dopamine (DA) cells, the excitatory effect of substance P and the inhibitory effect of Met-enkephalin on prefrontal cortical neurons, and the inhibitory effect of histamine on neurons of the sensorimotor cortex. In contrast, PROG blocked the excitatory effect of the C-terminal octapeptide of CCK in all 3 areas. Furthermore, iontophoretic PROG diminished, whereas CCK enhanced the inhibitory effect of similarly applied DA and GABA on DA cells. PROG pretreatment (1 mg/kg, i.v.) reduced the inhibitory potency and maximum effect of i.v. apomorphine (APO) on A9 DA neurons, while the inhibitory potency of APO was enhanced by i.v. CCK. Pretreatment with PROG plus CCK resulted in APO effects which were no different from those after PROG alone. Chronic treatment with PROG (1 mg/kg, p.o., 21 days) resulted in a return to normal of DA cell APO sensitivity. Combined, these findings suggest that PROG may be a relatively selective CCK antagonist, that the functional effect of dendritically released DA may be influenced by endogenously released CCK, and that tolerance may develop to the effects of chronic CCK receptor blockade.
最近的证据表明，谷氨酸衍生物丙谷胺（PROG）是大鼠中枢神经系统中胆囊收缩素（CCK）的选择性拮抗剂。现在已更详细地描述了这种选择性的程度。离子导入或静脉注射（i.v.）PROG对离子导入施加的神经降压素对中脑多巴胺（DA）细胞的兴奋作用、P物质的兴奋作用、甲硫氨酸脑啡肽对前额叶皮层神经元的抑制作用以及组胺对感觉运动皮层神经元的抑制作用均无效。相比之下，PROG在所有3个区域均阻断了CCK C末端八肽的兴奋作用。此外，离子导入的PROG减弱了，而CCK增强了同样施加的DA和GABA对DA细胞的抑制作用。PROG预处理（1mg/kg，静脉注射）降低了静脉注射阿扑吗啡（APO）对A9 DA神经元的抑制效力和最大效应，而静脉注射CCK增强了APO的抑制效力。PROG加CCK预处理产生的APO效应与单独使用PROG后的效应无差异。用PROG（1mg/kg，口服，21天）进行慢性治疗导致DA细胞对APO的敏感性恢复正常。综合这些发现表明，PROG可能是一种相对选择性的CCK拮抗剂，树突状释放的DA的功能效应可能受内源性释放的CCK影响，并且对慢性CCK受体阻断的效应可能会产生耐受性。
