Nicotinic Receptors in Parkinson's Disease

描述（由申请人提供）：我们的目标是确定烟碱受体亚型在基底神经节中的作用，并为帕金森病开发新的治疗策略。这项工作的基本原理是基于研究表明，尼古丁可以改善黑质纹状体损伤后的运动缺陷，此外，尼古丁或吸烟对啮齿动物和帕金森病的黑质纹状体损伤有明显的保护作用。然而，多种尼古丁受体被尼古丁激活，在外周和中枢神经系统中产生有益但也有副作用。我们假设大脑中特定的尼古丁受体群体参与了研究，研究表明不同的亚型具有独特的定位和分子功能。我们将通过四个具体目标来进行这些研究。作为关键的第一步，我们将确定基底神经节中烟碱受体亚型的区域和细胞定位，并确定黑质纹状体变性后受体亚型的变化。这将使用三种不同的方法完成，包括原位杂交，受体放射自显影和免疫细胞化学，并形成特异性目标1和2的基础。然后，我们将启动研究，评估与纹状体功能相关的尼古丁受体亚型，如Specific Aim 3所述，随后进行行为研究（Specific Aim 4），以确定尼古丁激动剂逆转帕金森病的能力。这项工作将增加我们对不同烟碱受体亚型在基底神经节功能中的作用的理解。

DESCRIPTION (provided by applicant): Our goal is to determine the role of nicotinic receptor subtypes in the basal ganglia with the long-term objective of developing novel therapeutic strategies for Parkinson's disease. The rationale for this work is based on studies showing that nicotine administration improves locomotor deficits after a nigrostriatal lesion and, furthermore, that nicotine or smoking results in an apparent protective effect against nigrostriatal damage in rodents and in Parkinson's disease. However, multiple nicotinic receptors are activated by nicotine to result in beneficial but also side effects in both the peripheral and central nervous system. We hypothesize that specific nicotinic receptor populations in the brain are involved based on work demonstrating that the distinct subtypes have unique localization and molecular functions. We will approach these studies through four specific aims. As a crucial first step, we will identify the regional and cellular localization of nicotinic receptor subtypes in basal ganglia and determine the changes in receptor subtypes after nigrostriatal degeneration. This will be done using three different approaches including in situ hybridization, receptor autoradiography and immunocytochemistry and form the basis of Specific Aims 1 and 2. We will then initiate studies to assess the nicotinic receptor subtypes involved in striatal function as described in Specific Aim 3, followed by behavioral studies (Specific Aim 4) to determine the ability of nicotinic agonists to reverse parkinsonism. This work should increase our understanding of the role of different nicotinic receptor subtypes in basal ganglia function. In summary, the proposed work should provide new insight concerning alterations in nicotinic receptor subtypes after nigrostriatal damage and nicotinic agonist treatment. These data together with the results of the behavioral studies may form a basis for the use of nicotinic drugs in the treatment of Parkinson's disease.