帕金森病（PD）的发病机制尚不明确，多种因素可能在PD发病过程中起作用。本项目基于囊泡单胺转运体（VMAT2）对多巴胺神经元的保护机制，在前期已研制VMAT2示踪药物的基础上，预实验发现当VMAT2被抑制时，大鼠对鱼藤酮（Rotenone，一种线粒体功能抑制剂）更加敏感，能够在更低的Rotenone剂量下产生PD。据此，我们提出科学假说：VMAT2和线粒体功能的联合抑制作用，可能是PD发病的主要因素之一。在本研究中，我们将利用小动物专用PET（microPET），在活体内、纵向跟踪研究实验动物在VMAT2抑制剂、Rotenone、以及二者联合给药等条件下，动物PD的发生、发展规律，系统研究实验动物的VMAT2功能、行为学以及其它PD相关分子生物学指标的变化趋势，揭示VMAT2在PD发生发展中的变化规律，阐明VMAT2在PD发病机制中的作用，为PD的预防和治疗研究提供新的思路。

The accurate mechanism of pathogenesis of Parkinson's disease (PD) is unclear. A variety of factors may play a role in the pathogenesis of PD. Recently, the protective function on dopamine (DA) neurons of the vesicular monoamine transporter (VMAT2) has been implicated a possible role in DA related disorders. We previously prepared a specific VMAT2 tracer, 18F-9-fluoropropyl-(+)-dihydrotetrabenzazine (18F-FP-(+)-DTBZ), in our lab. With the tracer at hand, we found that (1) rotenone, a biological toxicant used for prepare PD model, partly decreased VMAT2 function, (2) under condition of VMAT2 being inhibited, rats were more sensitive to produce PD after treated with rotenone, at a lower dose (0.5 vs 2.5 mg/kg/day). We now put forward our hypothesis that simultaneous inhibition of both VMAT2 and mitochondrial complex I (i.e. caused with rotenone) may be，or at least one of, the main factors of pathogenesis of PD. To prove our hypothesis, in this project, we will track the function of VMAT2 in rats in vivo longitudinally with a small animal PET (microPET) and 18F-FP-(+)-DTBZ during the process of animal rotenone PD model. Rats will be treated with (1) rotenone, (2) VMAT2 inhibitor, as well as (3) a combination of these two substance, and then followed with longitudinally monitoring of behavioral test, in vivo VMAT2 imaging with microPET, and other biomarkers analysis associated with PD. We want to map out law curves of the VMAT2 function during the PD occurrence and progression, and furtherly clarify the role of VMAT2 in pathogenesis of PD. The aim of this project is to confirm whether decrease of VMAT2 function with its inhibitor is a key determinant of PD pathogenesis. We hope our research give a new thinking for investigation of the prevention and therapy of PD.