Fuxe K, Agnati L F, Köhler C, Kuonen D, Ogren S O, Andersson K, Hökfelt T
J Neural Transm. 1981;51(1-2):3-37. doi: 10.1007/BF01664003.
Dopamine receptors have been characterized by the use of radiolabelled dopamine agonists and antagonists. Using ibotenic acid induced lesions of the striatum, evidence was obtained that 3H-N-propylnorapomorphine (3H-NPA) binding sites and 3H-bromocriptine binding sites are located both on intrastriatal nerve cells and on extrinsic nerve terminals probably mainly originating in the cerebral cortex. Development of dopamine receptor supersensitivity as evaluated in 6-hydroxydopamine lesioned rats was associated with an 50% increase in the number of 3H-NPA binding sites in the striatum. Furthermore, one year following the 6-hydroxydopamine induced lesion of the dopamine pathways two binding sites for 3H-NPA could be demonstrated in the striatum. However, at this time interval the total number of 3H-NPA binding sites was not increased. The functional significance of these two binding sites for 3H-NPA in the striatum is unknown, but they are probably coupled to the biological effector in view of the marked behavioural supersensitivity demonstrated in these old animals. The dopamine receptor agonists and especially the dopaminergic ergot derivatives have been characterized by studying their affinities for 3H-bromocriptine, 3H-spiperone, 3H-ADTN and 3H-NPA binding sites in vitro. It is suggested that the Ki ratios for agonist and antagonist radioligands may be one useful way to characterize the agonist-antagonist character of the drug. Another important method is to study the effects of dopamine receptor agonists on the specific in vivo binding of 3H-spiperone and 3H-NPA. The correlation analysis of DA agonist affinities for the four radioligands of DA receptors used in the present study give evidence for the existence of at least 3 types of DA receptors. Actions of dopaminergic ergot drugs have been evaluated at supersensitive dopamine receptors. The findings suggest that the shift to the left of the threshold dose to activate supersensitive dopamine receptors could be due to a lowering of the stereoselectivity of agonist interaction at the dopamine agonist sites of supersensitive dopamine receptors. Such a change may explain the highly preferential action of CF 25-397 at supersensitive dopamine receptors, since its affinity for 3H-NPA binding sites was not increased in the present experiments. In agreement with previous work, evidence have also been presented that prolonged treatment with a potent dopaminergic drug, pergolide, can produce a down regulation of normal dopamine receptors by reducing the density of such receptors. Evidence has also been presented that CCK-8 and the desulphated CCK-8 (10(-6) M) can in vitro reduce the number of 3H-NPA binding sites in the striatum. These results indicate that cholecystokinin peptides via activation of cholecystokinin receptors can regulate the movements of the 3H-NPA binding sites across the plane of the membrane in such a way as to make them less available to the external surface of the membrane...
通过使用放射性标记的多巴胺激动剂和拮抗剂，对多巴胺受体进行了表征。利用鹅膏蕈氨酸诱导的纹状体损伤，获得的证据表明，3H-N-丙基去甲阿扑吗啡（3H-NPA）结合位点和3H-溴隐亭结合位点既位于纹状体内神经细胞上，也位于可能主要起源于大脑皮层的外在神经末梢上。在6-羟基多巴胺损伤的大鼠中评估的多巴胺受体超敏反应的发展与纹状体中3H-NPA结合位点数量增加50%相关。此外，在6-羟基多巴胺诱导的多巴胺通路损伤一年后，纹状体中可显示出两个3H-NPA结合位点。然而，在此时间间隔，3H-NPA结合位点的总数并未增加。这两个纹状体中3H-NPA结合位点的功能意义尚不清楚，但鉴于这些老年动物表现出明显的行为超敏反应，它们可能与生物效应器偶联。通过研究多巴胺受体激动剂对3H-溴隐亭、3H-螺哌隆、3H-ADTN和3H-NPA结合位点的体外亲和力，对多巴胺受体激动剂，尤其是多巴胺能麦角衍生物进行了表征。有人提出，激动剂和拮抗剂放射性配体的Ki比值可能是表征药物激动剂-拮抗剂特性的一种有用方法。另一种重要方法是研究多巴胺受体激动剂对3H-螺哌隆和3H-NPA体内特异性结合的影响。本研究中使用的四种多巴胺受体放射性配体的多巴胺激动剂亲和力的相关分析证明至少存在3种类型的多巴胺受体。在超敏多巴胺受体上评估了多巴胺能麦角药物的作用。研究结果表明，激活超敏多巴胺受体的阈值剂量向左移动可能是由于超敏多巴胺受体的多巴胺激动剂位点上激动剂相互作用的立体选择性降低。这种变化可能解释了CF 25-397在超敏多巴胺受体上的高度优先作用，因为在本实验中其对3H-NPA结合位点的亲和力并未增加。与先前的工作一致，也有证据表明，用强效多巴胺能药物培高利特进行长期治疗可通过降低此类受体的密度来使正常多巴胺受体下调。也有证据表明，CCK-8和去硫酸化的CCK-8（10(-6) M）在体外可减少纹状体中3H-NPA结合位点的数量。这些结果表明，胆囊收缩素肽通过激活胆囊收缩素受体，可以调节3H-NPA结合位点跨膜平面的移动，使其不易暴露于膜的外表面……
