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: 6610371
• 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: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610371
• 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 其所有主要行动地点的本地化，因此 鉴定表达DA受体的细胞过程。 考虑到DA可以发出信号时，尤其如此 神经元通过非常规的神经传递形式 不受突触的约束。 我们建议利用 免疫细胞化学，电子显微镜和定量 立体图像分析以解决DA受体的问题 在大鼠和非人类灵长类动物的纹状体中定位。 我们 提出以下建议：（1）符合区分的资格 超微结构特征（维度，形态特征， 细胞过程免疫反应性的突触关联） 大鼠中的DA D1和D2受体，以彻底 记录正常的超微结构并提供基线 随后的物种和病变比较的信息。 我们 假设D2受体的定位将表明 DA通过更大程度的突触前和非突触作用 该受体亚型。 （2）确定超微结构如何 DA的细胞过程免疫反应性的特征 与大鼠相比，猴子的受体在猴子中是不同的。 我们 假设可比较的突触和非突触作用 这两个物种中的da将反映在类似的形态和 表达DA的细胞过程的突触关系 受体。 （3）使用双重标记免疫细胞化学 检查DA D1和D2共同分布的策略 具有谷氨酸NMDA和AMPA受体的受体。 基于 以前的生理数据，我们假设D1受体 将优先与NMDA受体共定位，而 D2受体将与两个NMDA进行非选择性分布 和AMPA受体。 （4）检查大鼠广泛 黑质纹状体DA途径的单侧病变 确定d1或d2的分布和形态如何 免疫反应过程发生了变化。 我们假设变化 在DA受体的分布和/或表达中将反映 更大程度的非突触传播，将被检测到 随着表达受体的细胞元素的改变及其 突触关系。 彻底无偏的定量 DA受体分布的测量对于 对这些问题和解释的统计有意义的分析 它们的含义的基础功能和基础病理学 神经节。