DOPAMINE RECEPTORS AND LESION INDUCED ALTERATIONS IN STRUCTURE AND EXPRESSION

多巴胺受体和损伤引起的结构和表达改变

• 批准号: 6323409
• 负责人: Susan R. Sesack
• 金额: $ 20.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6323409
• 关键词: 6 hydroxydopamine; AMPA receptors; Macaca fascicularis; NMDA receptors; Parkinson's disease; brain mapping; cellular pathology; corpus striatum; densitometry; dopamine receptor; electron microscopy; experimental brain lesion; image processing; immunocytochemistry; injection /infusion; innervation; laboratory rat; light microscopy; monoclonal antibody; neural plasticity; neural transmission; neuroanatomy; receptor expression; synapses; western blottings

Understanding the functions of dopamine (DA) requires the localization of all its major sites of action and hence, the identification of cellular processes that express receptors for DA. This is particularly true when considering that DA can signal neurons via unconventional forms of neurotransmission that are not constrained by synapses. We propose to utilize immunocytochemistry, electron microscopy, and quantitative stereological image analysis to address issues of DA receptor localization in the striatum of rats and non-human primates. We propose the following: (1) To qualify the distinguishing ultrastructural characteristics (dimensions, morphological features, and synaptic associations) of cellular processes immunoreactive for DA D1 and D2 receptors in the rat, in order to thoroughly document normal ultrastructure and to provide baseline information for subsequent species and lesion comparison. We hypothesize that the localization of D2 receptors will suggest a greater degree of presynaptic and non-synaptic actions of DA via this receptor subtype. (2) To determine how the ultrastructural characteristics of cellular processes immunoreactive for DA receptors are distinct in the monkey compared to the rat. We hypothesize that comparable synaptic and non-synaptic actions of DA in the two species will be reflected in similar morphology and synaptic relationships of the cellular processes expressing DA receptors. (3) To utilize a dual labeling immunocytochemical strategy to examine the co-distribution of DA D1 and D2 receptors with glutamate NMDA and AMPA receptors. Based on previous physiological data, we hypothesize that the D1 receptor will preferentially co-localize with the NMDA receptor, while the D2 receptor will be non-selectively distributed with both NMDA and AMPA receptors. (4) To examine rats with extensive unilateral lesions of the nigrostriatal DA pathway in order to determine how the distribution and morphology of D1- or D2 - immunoreactive processes is altered. We hypothesize that changes in the distribution and/or expression of DA receptors will reflect a greater degree of non-synaptic transmission and will be detectable as alterations in receptor-expressing cellular elements and their synaptic relationships. A thorough and unbiased quantitative measurement of DA receptor distribution is essential for statistically meaningful analyses of these issues and interpretation of their implications basic DA function and pathology of the basal ganglia.

了解多巴胺 (DA) 的功能需要 其所有主要作用场所的本地化，因此， 鉴定表达 DA 受体的细胞过程。 当考虑到 DA 可以发出信号时尤其如此 神经元通过非常规形式的神经传递 不受突触的限制。 我们建议利用 免疫细胞化学、电子显微镜和定量 体视图像分析解决 DA 受体问题 定位于大鼠和非人类灵长类动物的纹状体。 我们 建议如下： (1) 限定区分 超微结构特征（尺寸、形态特征、 和突触关联）的细胞过程的免疫反应 DA在大鼠体内的D1和D2受体，以便彻底 记录正常超微结构并提供基线 为后续物种和病变比较提供信息。 我们 假设 D2 受体的定位表明 DA 的更大程度的突触前和非突触作用 这种受体亚型。 (2) 确定超微结构 DA 免疫反应的细胞过程的特征 与大鼠相比，猴子的受体是不同的。 我们 假设可比较的突触和非突触行为 DA在两个物种中会体现出相似的形态和特征 表达 DA 的细胞过程的突触关系 受体。 (3) 利用双标记免疫细胞化学 检查 DA D1 和 D2 共同分布的策略 受体有谷氨酸 NMDA 和 AMPA 受体。 基于 根据之前的生理数据，我们假设 D1 受体 将优先与 NMDA 受体共定位，而 D2 受体将与 NMDA 一起非选择性分布 和 AMPA 受体。 (4) 检查大鼠的广泛性 黑质纹状体 DA 通路的单侧损伤 确定 D1- 或 D2- 的分布和形态 免疫反应过程发生改变。 我们假设变化 DA 受体的分布和/或表达将反映 更大程度的非突触传递并且可以被检测到 作为受体表达细胞元件及其变化 突触关系。 彻底且公正的定量 测量 DA 受体分布对于 对这些问题进行统计上有意义的分析和解释 其含义 基础 DA 功能和病理学 神经节。