PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

黑质和基底神经节的药理学和生理学

• 批准号: 3782300
• 负责人: J R WALTERS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3782300
• 关键词: 6 hydroxydopamine; apomorphine; basal ganglia; dopamine; dopamine agonists; dopamine receptor; electrophysiology; experimental brain lesion; fenoldopam; laboratory rat; neural transmission; neuropharmacology; neurophysiology; neurotransmitter metabolism; receptor expression; receptor sensitivity; reserpine; single cell analysis; substantia nigra

(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.

(1)基底节多巴胺(DA)D_1和D_2受体--体外研究： 在纹状体切片上的研究被用来研究机制。 这可能解释了D1激动剂对纹状体黑质的不同影响。 正常、6-羟基多巴胺损毁和利血平处理的大鼠的活动。 利用细胞内记录技术的实验发现如下 非诺多巴对纹状体神经元的影响 兴奋性没有改变，但SKF 38393表现出兴奋性和 抑制效应。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中介的 通过D1受体；结果引发了对体外使用的担忧 作为典型D1激动剂的SKF 38393的神经生理学研究。在……里面 相比之下，SKF 38393和非诺多巴可引起类似的变化 肌醇磷脂在对照组和对照组纹状体脑片中的蓄积 6-OHDA损毁大鼠；DA细胞损毁后这种蓄积更大。 (2)基底节中的D1和D2受体-活体研究：是否存在 损毁改变纹状体D2基因残存的稳态水平 有争议的。溶液杂交-核糖核酸酶保护分析发现 D2 Long或D2 Short的绝对计数没有显著差异 或以D2/β-肌动蛋白mRNAs比值表示 在损伤后2、4、8或19周对大鼠纹状体进行研究，表明 去多巴胺神经引起的突触后改变与 D2mRNA稳态水平的变化。 (3)DA激动剂的效应--丘脑底核：效应的检测 兴奋性氨基酸和多巴胺对丘脑底核神经元活动的影响 使用细胞外单单位记录技术显示，阻断 N-甲基-D-天冬氨酸或氨基-天冬氨酸受体的平均水平对 丘脑下层神经元的放电。DA激动剂阿朴吗啡，显著 增加丘脑下层神经元的放电，在光照下产生意想不到的效果 预测基底节组织数量增加的现有模型 多巴胺激动剂对苍白球下丘脑活动的抑制作用 行政管理。 (4)DA激动剂的作用--DA细胞：激动剂按相对大小排序 D2和D3受体的活性及其对DA细胞的抑制能力 开火。虽然D2受体在DA中的表达数量更多 到目前为止，D3受体的效力与ED50更好地相关 DA细胞抑制这些激动剂。