PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

1)D1型和D2型多巴胺受体在基底节的作用。机制 DL和D2受体的协同相互作用的基础是 通过细胞内记录技术在纹状体切片上进行研究， 今年对该科采取了新的方法。阴极脉冲会诱发至少两个 纹状体神经元的反应类型；与纹状体机制的相关性 将会被研究。局灶性刺激引起的EPSP至少由 三种可能；最快的似乎涉及非NMDA受体，即 较慢的电位涉及NMDA受体。局灶性电刺激也 似乎会释放一种调节因子，这种调节因子会导致 电流-电压关系。初步结果显示，多巴胺不是这样的。 但多巴胺似乎确实是一种调节因子 与电压相关的电导，并可调节重复点火 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 是目前临床上有意义的两种立体异构体；我们发现N-0923是一种 强效D2激动剂和N-0924作为部分D2激动剂。 突触前后D2受体备用受体数目的差异 部位解释了为什么部分多巴胺激动剂可以完全有效 在D2自体受体上，同时在突触后D2受体上提供“钳制”， 弱刺激，阻碍进一步刺激。事实上，维护 突触后多巴胺受体刺激或治疗水平 与部分多巴胺激动剂相比，阻断可能更有效 通过调节血液中更有效的药剂水平。 3)基底节多巴胺细胞变性的后果。变化 在慢性利血平治疗后的多巴胺受体功能 与那些在控制中看到的不同，但方向与 这些在长期6-羟基多巴胺损伤的大鼠中可见。类似的变化 是在有相对短期损伤的老鼠身上发现的 纹状体黑质通路。这是多巴胺存在双相模式的证据 多巴胺耗竭后受体介导的效应表明 对多巴胺丢失的代偿反应的范围和复杂性 之前很欣赏。 4)桥脑顶盖核(PPN)的作用。我们已经找到了 PPN对黑质多巴胺细胞活性的影响 通过间接和直接两种机制进行调解。这引发了一些问题 关于PPN退行性变在某些神经系统中的作用 疾病包括进行性核上性瘫痪、帕金森氏病和 阿尔茨海默氏症。

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.