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: 3922484
• 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/3922484
• 关键词: Parkinson's disease; basal ganglia; central nervous system; central nervous system disorders; centrally acting drug; corpus striatum; denervation; dopamine; dopamine receptor; drug metabolism; evoked potentials; experimental brain lesion; fluorimetry; gamma aminobutyrate; glutamate decarboxylase; laboratory rat; neurochemistry; neuromuscular disorder chemotherapy; neuropeptides; neuropharmacology; neurophysiology; neurotoxins; neurotransmitter biosynthesis; neurotransmitter metabolism; neurotransmitters; nontherapeutic iontophoresis; pilocarpine; probenecid; radioimmunoassay; radiotracer; substantia nigra; synapses

1) Roles of D-1 and D-2 Dopamine Receptors in Basal Ganglia. Concurrent D-1 and D-2 receptor stimulation is necessary for full expression of postsynaptic receptor-mediated effects of dopamine and dopamine agonists in the basal ganglia. Current results have indicated the interaction between the two receptor subtypes cannot be localized to the globus pallidus or the substantia nigra; it appears to take place in the striatum. 2) D-2 Autoreceptor/ D-2 Postsynaptic receptor Studies. The therapeutic potential of dopamine autoreceptor-selective drugs is of current concern. One factor contributing to the apparent ability of dopamine agonists with limited efficacy to selectively affect the dopamine autoreceptors is the existence of a greater D- 2 receptor reserve at dopamine autoreceptor sites relative to postsynaptic dopamine receptor sites. Two dopamine antagonists reported to selectively affect the autoreceptors do not appear selective for dopamine autoreceptors in our neurophysiological investigations. Thus, several factors make it possible for a drug to selectively affect dopamine autoreceptor-mediated function but current evidence does not suggest that the two receptors are structurally different. 3) Consequences of Dopamine Cell Degeneration in the Basal Ganglia. In an animal model of Parkinsonism, we have found neurophysiological evidence for functional up-regulation of GABA receptors in the nigra and down-regulation of these receptors and opioid receptors in the globus pallidus, correlating with decreased tonic level of activity in striatal input to the nigra and increased tonic inhibitory input to the globus pallidus. Support for the continued loss of dopamine terminals as a factor contributing to altered I-DOPA thresholds in advanced Parkinsonism was found in rats with bilateral dopamine cell lesions where I-DOPA is less effective than in unilaterally lesioned rats, presumably because of the small contralateral dopaminergic innervation unaffected by the unilateral lesion. 4) Role of the Pedunculopontine Tegmental Nucleus. A marked reduction in the number of spontaneously active dopamine cells was found in rats following kainic acid lesions of the pedunculopontine tegmental nucleus. Thus, this nucleus appears to exert a very significant tonic influence on substantia nigra dopamine cell activity.

1)D-1和D-2多巴胺受体在基底神经节中的作用 同时D-1和D-2受体刺激是必要的， 突触后受体介导的多巴胺效应的表达 和基底神经节的多巴胺激动剂 目前的结果有 表明两种受体亚型之间的相互作用不能 局限于苍白球或黑质;它 似乎发生在纹状体 2)D-2自身受体/ D-2突触后受体研究。 的 多巴胺自身受体选择性药物的治疗潜力， 目前的关注。 一个因素促成了明显的 具有有限功效的多巴胺激动剂选择性地 影响多巴胺自身受体的是更大的D- 2受体储备在多巴胺自身受体位点相对于 突触后多巴胺受体位点。 两种多巴胺拮抗剂 据报道，选择性地影响自动感受器， 选择性多巴胺自身受体在我们的神经生理 调查事务所 因此，有几个因素使药物 选择性地影响多巴胺自身受体介导的功能， 目前的证据并不表明这两种受体是 结构上不同。 3)基底部多巴胺细胞变性的后果 神经节 在帕金森症的动物模型中，我们发现 GABA功能上调的神经生理学证据 黑质中的受体和这些受体的下调， 苍白球中的阿片受体，与减少 纹状体向黑质输入的紧张性活动水平， 增加苍白球的紧张性抑制输入。 支持 多巴胺终末的持续丢失是一个因素， 导致晚期帕金森综合征I-DOPA阈值改变 在患有双侧多巴胺细胞病变的大鼠中发现， 可能比单侧损伤的大鼠效果更差， 因为对侧的多巴胺能神经分布很小 不受单侧病变的影响。 4)脚桥被盖核的作用。 明显 自发活动的多巴胺细胞数量减少， 在大鼠脚桥脑的红藻氨酸损伤后发现 被盖核 因此，这个核似乎发挥了非常大的作用， 对黑质多巴胺细胞有显著滋补作用 活动