Paul M L, Graybiel A M, David J C, Robertson H A
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
J Neurosci. 1992 Oct;12(10):3729-42. doi: 10.1523/JNEUROSCI.12-10-03729.1992.
Selective agonists for D1-like and D2-like dopamine receptors can interact synergistically to enhance each other's actions on locomotion and behavior in experimental animals. Clinically, the combination of the D2 agonist bromocriptine with L-dopa (which has pronounced D1 effects) is a highly effective treatment for Parkinson's disease. The mechanisms underlying this important receptor interaction are poorly understood and are the subject of intense study in vitro. In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway, D1-selective (but not D2-selective) dopamine agonists produce a marked increase in expression of the immediate-early gene c-fos in the striatum ipsilateral to the 6-OHDA lesion. In the experiments reported here, we have used this in vivo model to explore the possibility that combinations of D1-selective and D2-selective agonists might have effects on c-fos transcription that are different from those exhibited by D1 or D2 agonists administered alone. We examined the effects of the D1-selective agonist SKF-38393 and the D2-selective agonist quinpirole (LY 171555) on the expression of Fos-like protein and c-fos mRNA in the caudoputamen and made parallel behavioral observations in the same animals. A low dose of SKF-38393 produced little contraversive rotation and little induction of Fos-like immunoreactivity in the striatum. A low dose of quinpirole elicited contralateral rotation but little or no induction of Fos-like immunoreactivity in the caudoputamen; there was, however, induction of Fos in the globus pallidus ipsilateral to the 6-OHDA lesion. Combination of the low dose of SKF-38393 and quinpirole produced a synergistic effect on rotation and elicited, in the dopamine-depleted caudoputamen, a striking pattern of Fos-like protein expression in which Fos-positive neurons were concentrated in striosomes and in the dorsolateral caudoputamen. Northern blot analysis showed that c-fos mRNA was expressed following combined agonist treatment but was not detectable after the single-agonist treatments. Both the contraversive rotation and the induction of Fos-like immunoreactivity were blocked by the preadministration of the D1-preferring antagonist SCH-23390 and the D2-selective antagonist raclopride in combination. Pretreatment with the glutamate NMDA receptor antagonist MK-801 also blocked the induction of Fos-like immunoreactivity, and it reversed the rotation. These findings suggest a D1/D2 synergistic mechanism that involves the participation of D1-responsive striatonigral and D2-responsive striatopallidal output pathways, and that is sensitive to glutamatergic modulation.
D1样和D2样多巴胺受体的选择性激动剂可协同相互作用，增强彼此对实验动物运动和行为的作用。临床上，D2激动剂溴隐亭与左旋多巴（具有明显的D1效应）联合使用是治疗帕金森病的一种高效疗法。这种重要受体相互作用的潜在机制尚不清楚，是体外深入研究的主题。在黑质纹状体通路单侧6-羟基多巴胺（6-OHDA）损伤的大鼠中，D1选择性（而非D2选择性）多巴胺激动剂可使6-OHDA损伤同侧纹状体中即早基因c-fos的表达显著增加。在本文报道的实验中，我们利用这个体内模型来探究D1选择性和D2选择性激动剂联合使用可能对c-fos转录产生不同于单独给予D1或D2激动剂所表现出的影响的可能性。我们检测了D1选择性激动剂SKF-38393和D2选择性激动剂喹吡罗（LY 171555）对尾壳核中Fos样蛋白表达和c-fos mRNA的影响，并在同一动物中进行了平行的行为观察。低剂量的SKF-38393几乎不产生对侧旋转，也几乎不诱导纹状体中Fos样免疫反应性。低剂量的喹吡罗引起对侧旋转，但在尾壳核中几乎不诱导或不诱导Fos样免疫反应性；然而，在6-OHDA损伤同侧的苍白球中有Fos的诱导。低剂量的SKF-38393和喹吡罗联合使用对旋转产生协同作用，并在多巴胺耗竭的尾壳核中引发一种显著的Fos样蛋白表达模式，其中Fos阳性神经元集中在纹状体小体和背外侧尾壳核中。Northern印迹分析表明，联合激动剂处理后c-fos mRNA表达，但单激动剂处理后未检测到。对侧旋转和Fos样免疫反应性的诱导均被预先给予的D1优先拮抗剂SCH-23390和D2选择性拮抗剂雷氯必利联合阻断。用谷氨酸NMDA受体拮抗剂MK-801预处理也阻断了Fos样免疫反应性的诱导，并逆转了旋转。这些发现提示了一种D1/D2协同机制，该机制涉及D1反应性纹状体黑质和D2反应性纹状体苍白球输出通路的参与，并且对谷氨酸能调节敏感。
