Hu X T, White F J
Department of Psychiatry, Wayne State University School of Medicine, Detroit, Michigan.
Synapse. 1992 Mar;10(3):206-16. doi: 10.1002/syn.890100304.
Following 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) pathway, rat caudate-putamen (CPu) neurons are supersensitive to the inhibitory effects of both D1 and D2 dopamine (DA) receptor selective agonists. In addition, both the necessity of D1 receptor stimulation for D2 agonist-induced inhibition and the synergistic inhibitory effects of D1 and D2 agonists are abolished by denervation. The present study attempted to determine the relative roles of D1 and D2 DA receptors in the development of denervation supersensitivity to DA agonists and the "uncoupling" of functional interactions between the receptors following 6-OHDA lesions of the nigrostriatal DA pathway. Beginning on the day after an intraventricular 6-OHDA (or vehicle) injection, groups of rats received daily injections of either the selective D1 receptor agonist SKF 38393 (8.0 mg/kg, s.c.), the D2 agonist quinpirole (0.5 mg/kg, s.c.), or saline for 7 days. On the day following the last agonist injection, rats were anesthetized and prepared for extracellular single cell recording with iontophoretic drug administration. Daily administration of quinpirole selectively prevented the development of D2 receptor supersensitivity, whereas daily administration of SKF 38393 prevented the development of both D1 and D2 receptor supersensitivity. In addition, D1, but not D2, agonist treatment prevented the loss of synergistic inhibitory responses typically produced by 6-OHDA lesions. Behavioral observations revealed similar effects; daily injections of SKF 38393, but not quinpirole, prevented contralateral rotational responses to the mixed D1/D2 agonist apomorphine (1.0 mg/kg, s.c.) in rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. After a 4-week withdrawal from repeated D1 agonist treatment, both supersensitive inhibitory responses of CPu neurons and contralateral rotations to apomorphine were evident, indicating that the preventative effects on DA receptor supersensitivity were not permanent. These findings indicate that continued agonist occupation of striatal D1 DA receptors following DA denervation not only prevents the development of D1 DA receptor supersensitivity but also exerts a similar regulation of D2 receptor sensitivity.
在黑质纹状体多巴胺（DA）通路经6-羟基多巴胺（6-OHDA）损伤后，大鼠尾状核-壳核（CPu）神经元对D1和D2多巴胺（DA）受体选择性激动剂的抑制作用均表现出超敏反应。此外，去神经支配消除了D1受体刺激对D2激动剂诱导的抑制作用的必要性以及D1和D2激动剂的协同抑制作用。本研究试图确定D1和D2 DA受体在对DA激动剂去神经超敏反应的发展以及黑质纹状体DA通路经6-OHDA损伤后受体之间功能相互作用的“解偶联”中的相对作用。从脑室内注射6-OHDA（或溶剂）后的第二天开始，将大鼠分组，每天皮下注射选择性D1受体激动剂SKF 38393（8.0 mg/kg）、D2激动剂喹吡罗（0.5 mg/kg）或生理盐水，持续7天。在最后一次激动剂注射后的第二天，将大鼠麻醉并准备进行离子电泳给药的细胞外单细胞记录。每天给予喹吡罗可选择性地阻止D2受体超敏反应的发展，而每天给予SKF 38393可阻止D1和D2受体超敏反应的发展。此外，D1激动剂治疗可阻止通常由6-OHDA损伤产生的协同抑制反应的丧失，但D2激动剂治疗则不能。行为观察显示出类似的效果；每天皮下注射SKF 38393可阻止黑质纹状体通路单侧6-OHDA损伤的大鼠对混合D1/D2激动剂阿扑吗啡（1.0 mg/kg）产生对侧旋转反应，但喹吡罗则不能。在重复D1激动剂治疗停药四周后，CPu神经元的超敏抑制反应和对阿扑吗啡的对侧旋转反应均很明显，这表明对DA受体超敏反应的预防作用不是永久性的。这些发现表明，DA去神经支配后持续用激动剂占据纹状体D1 DA受体不仅可阻止D1 DA受体超敏反应的发展，还对D2受体敏感性发挥类似的调节作用。
