Chipkin R E, McQuade R D, Iorio L C
Schering Corporation, Department of Pharmacology, Bloomfield, NJ 07003.
Pharmacol Biochem Behav. 1987 Dec;28(4):477-82. doi: 10.1016/0091-3057(87)90509-0.
Treatments with drugs to up-regulate specific receptors is a strategy often employed in mechanism of action studies. In this type of experiment, changes in the numbers of receptors and concomitant changes in an animal's sensitivity to the drug have been used as evidence for the participation of the binding site in the behavior. In these studies, to test for the role of D1 and D2 receptors in apomorphine-induced stereotypy (AIS), dopamine binding sites were up-regulated by appropriate pre-treatments and the ability of these pre-treatments to alter AIS was subsequently investigated. In the first experiment, 19 days of pre-treatment with SCH 23390 or haloperidol selectively increased by 35 and 40% the numbers of striatal D1 and D2 binding sites, respectively, without affecting their affinities. However, when challenged with apomorphine, only the animals pre-treated with the D2 antagonist showed behavioral supersensitivity. In the second experiment, reserpine pre-treatment (30 mg/kg IP, 24-hr pre-test) increased the numbers of D1 binding sites by 18%, but did not significantly alter the numbers of striatal D2 binding sites. Behaviorally, these rats were supersensitive to apomorphine's stereotypy-inducing effects; however, they also showed an increased sensitivity to the ability of either haloperidol or SCH 23390 to block AIS. Moreover, this blockade was only attenuated by a D2 (but not a D1) agonist. Collectively, these data suggest that AIS is mediated by both D1 and D2 binding sites, but that D2 binding sites have a more important role.
使用药物上调特定受体是作用机制研究中经常采用的一种策略。在这类实验中，受体数量的变化以及动物对药物敏感性的相应变化被用作结合位点参与行为的证据。在这些研究中，为了测试D1和D2受体在阿扑吗啡诱导的刻板行为（AIS）中的作用，通过适当的预处理上调多巴胺结合位点，随后研究这些预处理改变AIS的能力。在第一个实验中，用SCH 23390或氟哌啶醇预处理19天，分别使纹状体D1和D2结合位点的数量选择性增加35%和40%，而不影响它们的亲和力。然而，当用阿扑吗啡进行激发时，只有用D2拮抗剂预处理的动物表现出行为超敏反应。在第二个实验中，利血平预处理（腹腔注射30mg/kg，预测试前24小时）使D1结合位点的数量增加了18%，但没有显著改变纹状体D2结合位点的数量。在行为上，这些大鼠对阿扑吗啡的刻板行为诱导作用超敏；然而，它们对氟哌啶醇或SCH 23390阻断AIS的能力也表现出增加的敏感性。此外，这种阻断仅被D2（而非D1）激动剂减弱。总体而言，这些数据表明AIS由D1和D2结合位点介导，但D2结合位点具有更重要的作用。
