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，长期目标是开发帕金森病的新治疗策略。这项工作的基本原理是基于研究表明，尼古丁给药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，多种烟碱受体被烟碱激活，从而在外周和中枢神经系统中产生有益的但也有副作用。我们假设，特定的烟碱受体群体在大脑中的工作表明，不同的亚型具有独特的定位和分子功能的基础上参与。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，我们将确定区域和基底神经节烟碱受体亚型的细胞定位，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，并构成特定目的1和2的基础。然后，我们将启动研究，以评估参与纹状体功能的烟碱受体亚型，如具体目标3所述，随后进行行为研究（具体目标4），以确定烟碱受体激动剂逆转帕金森综合征的能力。这项工作应该增加我们的理解不同的烟碱受体亚型在基底神经节功能的作用。 总之，拟议的工作应该提供新的见解有关黑质纹状体损伤和烟碱激动剂治疗后烟碱受体亚型的改变。这些数据与行为研究的结果一起可能构成使用烟碱类药物治疗帕金森病的基础。

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.