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: 3881688
• 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/3881688
• 关键词: Alzheimer's disease; GABA receptor; NMDA receptors; Parkinson's disease; basal ganglia; cerebral palsy; corpus striatum; dihydroxyphenylalanine; dopamine; dopamine receptor; electrical potential; laboratory rat; neural degeneration; neurochemistry; neuromuscular disorder chemotherapy; neuropharmacology; neurophysiology; neurotransmitter metabolism; opioid receptor; pons; receptor expression; receptor sensitivity; stimulant /agonist; substantia nigra; synapses; tegmentum

1) Roles of Dl and D2 Dopamine Receptors in Basal Ganglia. Mechanisms underlying the synergistic interactions of Dl and D2 receptors are being studied in striatal slices via intracellular recording techniques, an approach new to the Section this year. Cathodal pulses induce at least two types of response in the striatal neurons; relevance to striatal mechanisms will be studied. Focal stimulation elicits EPSP's composed of at least three potentials; the fastest appears to involve a non-NMDA receptor, the slower potentials involve NMDA receptors. Focal electrical stimulation also appears to release a modulatory factor which induces changes in current-voltage relationships. First results show that dopamine is not this modulatory factor but dopamine does appear to be a modulator of the voltage-dependent conductances and may regulate repetitive firing in striatal neurons. 2) D2 Autoreceptor / D2 Postsynaptic Receptor Studies. N-0923 and N-0924 are two stereoisomers of current clinical interest; we find N-0923 is a potent and efficacious D2 agonist and N-0924 acts as a partial D2 agonist. Differences in spare receptor number at pre- and post-synaptic D2 receptor sites account for why a partial dopamine agonist can be fully efficacious at D2 autoreceptors while providing a "clamp" at postsynaptic D2 receptors, stimulating weakly while blocking further stimulation. In fact, maintaining therapeutic levels of postsynaptic dopamine receptor stimulation or blockade may be more effectively done with partial dopamine agonists than by adjustment of blood levels of more efficacious agents. 3) Consequences of Dopamine Cell Degeneration in the Basal Ganglia. Changes in dopamine receptor function following chronic reserpine treatment are different from those seen in control but in the opposite direction from those seen in long term 6-hydroxydopamine lesioned rats. Similar changes are being found in rats with relatively short-term lesions of the striatonigral pathway. This evidence for a biphasic pattern in dopamine receptor-mediated effects after dopamine depletion indicates a greater range and complexity in the compensatory responses to dopamine loss than previously appreciated. 4) Role of the Pedunculopontine Tegmental Nucleus (PPN). We have found the PPN exerts effects on substantia nigra dopamine cell activity which appear mediated by both indirect and direct mechanisms. This raises questions about the role of PPN degeneration shown occurring in certain neurological disorders including progressive supranuclear palsy, Parkinson's disease and Alzheimer's disease.

1)D1和D2多巴胺受体在基底神经节中的作用。机制 作为D1和D2受体协同相互作用的基础， 通过细胞内记录技术研究纹状体切片， 今年新加入的部门。阴极脉冲诱导至少两个 纹状体神经元的反应类型;与纹状体机制的相关性 将被研究。局灶性刺激诱发EPSP至少由以下部分组成： 三种电位;最快的似乎涉及非NMDA受体， 慢电位涉及NMDA受体。局灶性电刺激还 似乎释放了一种调节因子， 电流-电压关系第一个结果表明多巴胺不是 调节因子，但多巴胺似乎是一种调节剂， 依赖于电压的电导，并可以调节重复点火， 纹状体神经元 2)D2自身受体/ D2突触后受体研究。N-0923和N-0924 是目前临床感兴趣的两种立体异构体;我们发现N-0923是一种 N-0924作为D2部分激动剂。 突触前和突触后D2受体上备用受体数量的差异 位点解释了为什么部分多巴胺激动剂可以完全有效 同时在突触后D2受体上提供“钳夹”， 微弱地刺激，同时阻断进一步的刺激。事实上，维护 治疗水平的突触后多巴胺受体刺激或 部分多巴胺受体激动剂的阻断效果可能比 通过调节更有效药剂的血液水平。 3)基底神经节多巴胺细胞变性的后果。变化 在多巴胺受体功能的慢性利血平治疗后， 与对照组不同，但方向相反， 在长期6-羟基多巴胺损伤的大鼠中观察到的那些。类似的变化 在大鼠中发现， 纹状体黑质通路这是多巴胺双相模式的证据 多巴胺耗竭后受体介导的效应表明， 对多巴胺丧失的代偿反应的范围和复杂性 以前赞赏。 4)脚桥被盖核（Pedunculopontine Tegmental Nucleus，PPN）我们遇见 PPN对黑质多巴胺细胞活性产生影响， 通过间接和直接机制介导。这引发了一些问题 PPN变性在某些神经系统疾病中的作用 包括进行性核上性麻痹、帕金森病和 老年痴呆症