DOPAMINE D1, D2, AND D3 RECEPTORS AS BIOMARKERS FOR IMAGING NIGROSTRIATAL NEURONS

多巴胺 D1、D2 和 D3 受体作为黑质纹状体神经元成像的生物标志物

• 批准号: 8807974
• 负责人: Jinbin Xu
• 金额: $ 7.63万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8807974
• 关键词: Accounting; Affect; Agonist; Behavioral; Biological Markers; Brain; Carbidopa; Carboxy-Lyases; Cell Count; Cerebrum; Chronic; Corpus striatum structure; Data Analyses; Denervation; Disease; Disease Progression; Dopamine; Dopamine Agonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Dopaminergic Agents; Dose; Freezing; Functional disorder; Goals; Grant; Image; In Vitro; Injury; Intervention; Lead; Levodopa; Measurement; Measures; Monitor; Monkeys; Motor; Neurodegenerative Disorders; Neurons; Neurotoxins; North America; Output; Parkinson Disease; Parkinsonian Disorders; Placebos; Play; Positron-Emission Tomography; Procedures; Quantitative Autoradiography; Regulation; Research; Role; Severities; Severity of illness; Substantia nigra structure; Syndrome; Time; Tissues; Tracer; Tyrosine 3-Monooxygenase; brain tissue; density; dopamine D3 receptor; dopaminergic neuron; in vivo; neuroimaging; neuron loss; novel; postsynaptic; pramipexol; presynaptic; public health relevance; receptor; receptor density; receptor expression; receptor function; therapy development; transmission process; uptake; vesicular monoamine transporter

DESCRIPTION (provided by applicant): Parkinson Disease (PD), the second most common neurodegenerative disease, affects more than one million people in North America, and no treatment has been proven to slow progression. Neuroimaging biomarkers have the potential to provide unbiased measurements of PD progression. Changes in dopamine receptors related to loss of nigrostriatal neurons may lead to "dysregulation" of dopamine D2 and D3 receptors with a change in the D2:D3 ratio. A change in the D2:D3 ratio may play a key role in the behavioral consequences of CNS syndromes characterized by altered D2-like receptor function. However, the precise role of D3 in the pathophysiology and treatment remains to be determined. We previously developed a novel procedure to measure the density of D2 and D3 receptors in vitro and found that D3 receptors in striatum and substantia nigra change differently from D1 and D2 receptors in PD brains. We previously evaluated three different presynaptic PET tracers, [11C]DTBZ, [11C]CFT and [18F]fluoroDOPA for nigrostriatal neurons in monkeys given a wide range of doses of the selective dopaminergic neurotoxin MPTP. These PET studies demonstrated that striatal uptake of each of these linearly correlates with the number of nigrostriatal neurons (using unbiased stereologic counts of tyrosine hydroxylase [TH] immunostained neurons in nigra) but only when the loss of nigrostriatal neurons does not exceed 50%. In contrast, each of these tracers linearly correlates with in vitro measures of striatal dopamine. The in vivo PET measures correlated well with each other and with quantitative autoradiography of VMAT2 and DAT in striatum. Interestingly, motor ratings correlated fully with nigral cell counts and not with striatal dopamine or other terminal field measures, suggesting that factors other than just loss of striatal terminal fields influence motor parkinsonism. We hypothesize that changes in postsynaptic dopamine receptors may account for this discrepancy. In this project, we propose to conduct quantitative autoradiography measures of the postsynaptic dopamine receptors (D1, D2 and D3) in the striatum from brain tissues from 41 monkeys, 16 of them are treated with a wide range of single internal carotid MPTP doses (0 to 0.31 mg/kg); 10 of them will be studied at different times after a MPTP (5 at 10 days and 5 at 3 weeks); 3 groups of 5 will have a single dose of MPTP then treated for 2 months with chronic levodopa, a dopamine receptor agonist pramipexole or placebo. These additional measures are expected to provide a more complete reflection of the state of nigrostriatal neurons than presynaptic measures alone. The overall goal of this 2-year project is to determine how postsynaptic markers change after dopamine denervation to determine the most effective neuroimaging measures for accurate measurement of the severity of nigrostriatal injury. We also will investigate the effects chronic treatment with levodopa or pramipexole (a dopamine D3 receptor agonist) on these markers. The studies proposed in this grant have great potential for extending our understanding of the functional roles of dopamine receptor subtypes in PD progression.

描述（由申请人提供）：帕金森病 (PD) 是第二常见的神经退行性疾病，影响北美超过一百万人，并且没有任何治疗方法被证明可以减缓进展。神经影像生物标志物有潜力提供 PD 进展的公正测量。与黑质纹状体神经元损失相关的多巴胺受体变化可能导致多巴胺 D2 和 D3 受体“失调”，并导致 D2:D3 比例发生变化。 D2:D3 比例的变化可能在以 D2 样受体功能改变为特征的 CNS 综合征的行为后果中发挥关键作用。然而，D3 在病理生理学和治疗中的确切作用仍有待确定。我们之前开发了一种新的方法来测量体外 D2 和 D3 受体的密度，发现纹状体和黑质中的 D3 受体的变化与 PD 大脑中的 D1 和 D2 受体不同。我们之前评估了给予大范围剂量的选择性多巴胺能神经毒素 MPTP 的猴子黑质纹状体神经元的三种不同的突触前 PET 示踪剂，[11C]DTBZ、[11C]CFT 和 [18F]氟多巴。这些 PET 研究表明，纹状体对这些物质的摄取与黑质纹状体神经元的数量呈线性相关（使用黑质中酪氨酸羟化酶 [TH] 免疫染色神经元的无偏立体学计数），但前提是黑质纹状体神经元的损失不超过 50%。相反，这些示踪剂中的每一个都与纹状体多巴胺的体外测量值线性相关。体内 PET 测量结果彼此相关，并且与纹状体中 VMAT2 和 DAT 的定量放射自显影相关。有趣的是，运动评级与黑质细胞计数完全相关，而不与纹状体多巴胺或其他终场测量相关，这表明除了纹状体终场丧失之外还有其他因素影响运动帕金森症。我们假设突触后多巴胺受体的变化可能解释了这种差异。在这个项目中，我们建议对 41 只猴子的脑组织纹状体中的突触后多巴胺受体（D1、D2 和 D3）进行定量放射自显影测量，其中 16 只猴子接受了大范围的单一颈内动脉 MPTP 剂量（0至 0.31 毫克/千克）；其中 10 个将在 MPTP 后的不同时间进行研究（5 个在 10 天，5 个在 3 周）； 3 组（每组 5 人）将接受单剂 MPTP，然后接受慢性左旋多巴、多巴胺受体激动剂普拉克索或安慰剂治疗 2 个月。这些额外的测量预计将比单独的突触前测量更完整地反映黑质纹状体神经元的状态。这个为期两年的项目的总体目标是确定多巴胺去神经后突触后标记物如何变化，以确定最有效的神经影像学措施，以准确测量黑质纹状体损伤的严重程度。我们还将研究左旋多巴或普拉克索（多巴胺 D3 受体激动剂）长期治疗对这些标记物的影响。本次资助中提出的研究对于扩展我们对多巴胺受体亚型在帕金森病进展中功能作用的理解具有巨大的潜力。