PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

(1)基底神经节中的D1和D2多巴胺（DA）受体--体外研究： 纹状体切片的研究进行了调查机制 这可能解释了D1激动剂对纹状体黑质的不同作用， 在正常、6-OHDA损伤和利血平处理的大鼠中的活性。 利用细胞内记录技术的实验发现， DA细胞损伤，非诺多泮对纹状体神经元的影响 兴奋性没有改变，但SKF 38393既表现出兴奋性， 抑制作用D1拮抗剂SCH 23390未能逆转SKF 38393-诱导的兴奋性变化表明它们不是介导的 通过D1受体;结果引起了对体外使用的担忧 SKF 38393作为原型D1激动剂的神经生理学研究。在 相比之下，SKF 38393和非诺多泮诱导的 对照组纹状体切片中的磷酸肌醇积累， 6-OHDA损伤大鼠; DA细胞损伤后，这种蓄积更大。 (2)基底神经节中的D1和D2受体-体内研究： 损伤改变了纹状体D2 mRNA的稳态水平， 争议溶液杂交-核糖核酸酶保护试验发现 D2长或D2短的绝对计数无显著差异 mRNA或D2/β-肌动蛋白mRNA的比值 损伤后2、4、8或19周研究大鼠纹状体，表明 DA去神经诱导的突触后变化与 D2 mRNA稳态水平的改变。 (3)DA受体激动剂的作用-丘脑底核：作用检查 兴奋性氨基酸和多巴胺对丘脑底核神经元活动的影响 使用细胞外单个单位记录技术显示， NMDA或AMPA受体的平均水平对 丘脑底核神经元的放电多巴胺受体激动剂阿扑吗啡， 增加了丘脑底神经元的放电， 目前的基底神经节组织模型预测， DA受体激动剂对苍白球底丘脑活性的抑制作用 局 (4)DA激动剂的作用- DA细胞：根据相对生物学活性对激动剂进行排序。 对D2和D3受体的效力，并检查抑制DA细胞的能力 击发尽管D2受体在多巴胺受体中表达的数量更多， 细胞，迄今为止，D3受体的效价与ED 50相关性更好， DA细胞抑制这些激动剂。

(1) D1 and D2 Dopamine (DA) Receptors in Basal Ganglia-~ in vitro Studies: Studies in striatal slices were undertaken to investigate mechanisms which might account for different effects of D1 agonists on striatonigral activity in normal, 6-OHDA-lesioned, and reserpine-treated rats. Experiments utilizing intra-cellular recording techniques find, following DA cell lesion, that fenoldopam's effects on striatal neuronal excitability are not altered, but SKF 38393 exhibited both excitatory and inhibitory effects. The D1 antagonist SCH 23390 failed to reverse SKF 38393-induced changes in excitability indicating they are not mediated through D1 receptors; results raise concern about use in vitro neurophysiological studies of SKF 38393 as a prototypic D1 agonist. In contrast, SKF 38393 and fenoldopam induced comparable changes in phosphoinositide accumulation in striatal slices from control and 6-OHDA-lesioned rats; this accumulation is greater after DA cell lesion. (2) D1 and D2 Receptors in Basal Ganglia - in vivo Studies: Whether the lesion alters the steady-state levels of striatal D2 mRNA remains controversial. Solution hybridization-ribonuclease protection assays found no significant differences in absolute counts for D2 long or D2 short mRNAs or in ratios of D2/beta-actin mRNAs between lesioned and unlesioned striata in rats studied 2, 4, 8 or 19 weeks after lesion, indicating that postsynaptic changes induced by DA denervation are not associated with alterations in steady-state levels of D2 mRNA. (3) Effects of DA Agonists - Subthalamic Nucleus: Examination of effects of excitatory amino acids and DA on the activity of subthalamic neurons using extracellular single unit recording techniques showed that blockade of NMDA or AMPA receptors had no significant effect on average on the firing of subthalamic neurons. The DA agonist, apomorphine, significantly increased the firing of subthalamic neurons, effects unexpected in light of current models of basal ganglia organization that predict increased inhibitory pallidosubthalamic activity following DA agonist administration. (4) Effects of DA Agonists - DA Cells: Agonists were ranked for relative potency at D2 and D3 receptors and examined for ability to inhibit DA cell firing. Although D2 receptors are expressed in greater numbers by DA cells, to date potency at D3 receptors correlates better with the ED50 for DA cell inhibition of these agonists.