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: 3860765
• 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/3860765
• 关键词: NMDA receptors; basal ganglia; caudate nucleus; corpus striatum; dizocilpine; dopamine; dopamine receptor; laboratory rat; lenticular nucleus; neural transmission; neurons; neuropharmacology; neurophysiology; neurotransmitter metabolism; receptor sensitivity; stimulant /agonist; substantia nigra

1) Dl and D2 Dopamine Receptors in Basal Ganglia: in Vitro Studies. Studies in striatal slices utilizing intracellular recording techniques confirm that Dl stimulation typically exerts an inhibitory effect on striatal neurons with dopaminergic innervation intact. In contrast, the majority of striatal neurons in tissue ipsilateral to 6 week 6-hydroxydopamine (6-OHDA) lesions respond to a Dl agonist, SKF 38393, with an increase in excitability, suggesting that a dramatic difference in the function of the striatal Dl receptors or coupled intracellular processes occurs following dopaminergic denervation. If confirmed, these findings will be the first in vitro evidence to indicate that chronic dopaminergic denervation changes the predominant effect of D1 stimulation in the striatum from inhibition to excitation. 2) Consequences of Dopamine Depletion in the Basal Ganglia. Two strategies for depleting dopamine, 6-OHDA-induced dopamine cell lesion and subchronic treatment with reserpine, are thought to induce comparable behavioral indications of dopamine receptor supersensitivity. However, in 6-OHDA-lesioned rats, a Dl agonist produces a decrease in rate in the substantia nigra pars reticulata while in the reserpine-treated rats an increase in the firing rates of cells in the substantia nigra pars reticulata occurs. Thus, through as yet unidentified processes, these two strategies for depleting dopamine exert different effects on Dl-mediated mechanisms resulting in opposite changes in basal ganglia output. 3) Role of Excitatory Amino Acid Receptor Subtypes, AMPA and NMDA in Basal Ganglia Function. The NMDA antagonist MK 801 alters the effects of apomorphine on type I caudate neurons and on Type II globus pallidus neurons. MK 801 also completely blocks the Dl agonist SKF 38393's inhibitory effect on dopamine cells and excitatory effect on reticulata cells in reserpine-treated rats. in addition, MK 801 blocks the inhibitory effect of the Dl agonist on reticulata cells in 6-OHDA lesioned rats. These results provide evidence for an apparent dependence of dopamine-mediated effects in the basal ganglia on tonic glutamatergic activity and indicate that blockade of NMDA receptors "upstream" from the globus pallidus interferes with dopamine-mediated neuronal transmission through the neostriatum. In contrast, the AMPA antagonist, NBQX inhibits the firing rate of both Type I caudate neurons and Type 11 globus pallidus cells but does not alter their response to apomorphine.

1)基底神经节中的D1和D2多巴胺受体：体外研究。 纹状体脑片细胞内记录技术的研究 证实了D1刺激通常对D1受体发挥抑制作用。 多巴胺能神经支配完好的纹状体神经元。 而反观 大部分纹状体神经元在6周的同侧组织中 6-羟基多巴胺（6-OHDA）损伤对D1激动剂SKF 38393有反应， 兴奋性的增加，这表明，一个戏剧性的差异， 纹状体D1受体或偶联的细胞内过程的功能 发生在多巴胺能神经切断之后。 如果得到证实，这些发现 将是第一个体外证据表明慢性多巴胺能 去神经支配改变了D1刺激的主要作用， 纹状体从抑制到兴奋。2)多巴胺的后果 基底神经节衰竭。 两种消耗多巴胺的方法， 6-OHDA-诱导的多巴胺细胞损伤和亚慢性治疗 利血平，被认为是诱导类似的行为指标， 多巴胺受体超敏反应 然而，在6-OHDA损伤的大鼠中， 激动剂引起黑质网状部速率降低 而在利血平处理的大鼠中， 黑质网状部的细胞发生。 因此，到目前为止， 这两种消耗多巴胺的策略 对DI介导的机制的不同影响导致相反的变化 基底神经节输出。3)兴奋性氨基酸受体的作用 亚型、AMPA和NMDA与基底神经节功能 NMDA拮抗剂MK 801改变阿扑吗啡对I型尾状核神经元和I型尾状核神经元的作用 苍白球神经元。 MK 801还完全阻断D1激动剂 SKF 38393对多巴胺细胞的抑制作用和对 利血平处理大鼠的网状细胞。此外，MK 801还能阻止 D1激动剂对6-OHDA损伤的网状细胞的抑制作用 大鼠 这些结果提供了明显依赖于 多巴胺介导的基底神经节对强直性多巴胺能神经元的作用 活性，并表明阻断NMDA受体的“上游”，从 苍白球干扰多巴胺介导的神经元传递 穿过新纹状体 相反，AMPA拮抗剂NBQX抑制了 I型尾状核神经元和11型苍白球神经元的放电频率 细胞，但不改变它们对阿扑吗啡的反应。