MESOLIMBIC DOPAMINE D3 RECEPTOR AND PARKINSON'S DISEASE

中脑边缘多巴胺 D3 受体与帕金森病

• 批准号: 6394298
• 负责人: JEFFREY N JOYCE
• 金额: $ 35.45万
• 依托单位: BANNER SUN HEALTH RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-25 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6394298
• 关键词: Parkinson's disease; antiparkinson drugs; clinical research; dementia; dopamine receptor; drug resistance; human tissue; molecular pathology; pathologic process; postmortem; receptor expression

DESCRIPTION: (Adapted from the Investigator's Abstract): Most symptoms of Parkinson's Disease (PD) are thought to occur as a result of loss of the nigrostriatal dopaminergic pathway. However, it is now evident that for many PD patients failure of response to antiparkinsonian medication is linked to spreading of pathology to other dopamine (DA) systems, and, possibly to changes in expression of postsynaptic DA receptors. It has been proposed that rigidity, tremor and secondary akinesia start first with degeneration of the nigrostriatal DA system followed by spread of the pathology to the mesolimbic DA system, which may produce primary akinesia, dementia and depression. This spreading of pathology from one functional system to another might be one of the key factors responsible for the progressive worsening of the motoric symptoms and increase in non-responders with disease duration. However, research on changes in postsynaptically located DA receptors has focused on contributions of the D2 receptor to changes in Parkinsonian symptoms, and it has been specifically hypothesized that loss of responsiveness in late-stage PD results from reduced D2 receptor number. Our evidence shows that another member of the D2 receptor family, the D3 receptor, which is a target receptor for the mesolimbic DA system, plays a predominant role in the deteriorated response of L-dopa and DA agonists in advanced PD. We will test if disease related changes in the postsynaptic (loss of D3 receptor), as well as presynaptic, components of the mesolimbic DA system contribute to the loss of effective response of antiparkinsonian medication in PD patients, and to the presence of dementia. The present research is therefore focused on postmortem studies that provide: (1) identification of changes in D3 receptor expression in subgroups of PD; (2) identifying changes in the expression of D3 receptor mRNA relative to D, and D2 receptor mRNAs in striatal-pallidal-thalmo pathways; (3) relationship of changes in D3 receptor expression and clinical symptoms to loss of mesolimbic DA system; and (4) use of experimental models of PD to study regulation of the D3 receptor, and identify why antiparkinsonian medication eventually fails to upregulate this receptor. This will further elucidate the pathology of DAergic substrates of specific clinical symptoms in PD and provide a broader basis for developing effective treatment strategies based on specific DA receptors.

描述：（改编自研究者摘要）：大多数症状 帕金森病 (PD) 被认为是由于失去 黑质纹状体多巴胺能通路。然而，现在很明显，对于许多 PD 患者对抗帕金森病药物反应失败与 将病理学传播到其他多巴胺 (DA) 系统，并可能导致变化 突触后 DA 受体的表达。有人提出，刚性， 震颤和继发性运动运动首先从肌腱退化开始 黑质纹状体 DA 系统随后病理学扩散至中脑边缘 DA系统，可能产生原发性运动不能、痴呆和抑郁症。这 病理从一个功能系统传播到另一个功能系统可能是其中之一 导致运动功能逐渐恶化的关键因素 随着疾病持续时间的推移，症状和无反应的情况会增加。然而， 关于突触后 DA 受体变化的研究主要集中在 D2 受体对帕金森症状变化的贡献 特别假设晚期 PD 反应能力丧失 D2 受体数量减少的结果。我们的证据表明另一名成员 D2 受体家族中的 D3 受体是 中脑边缘 DA 系统在反应恶化中起主要作用 左旋多巴和 DA 激动剂治疗晚期 PD。我们将测试是否与疾病相关的变化 在突触后（D3 受体缺失）以及突触前成分 中脑边缘 DA 系统的缺失导致有效反应的丧失 PD 患者服用抗帕金森病药物，以及是否存在痴呆。 因此，目前的研究重点是尸检研究，这些研究提供： (1) 鉴定PD亚组中D3受体表达的变化； (2) 鉴定 D3 受体 mRNA 相对于 D 和 D2 的表达变化 纹状体-苍白球-丘脑通路中的受体 mRNA； (3)关系 D3 受体表达和临床症状的变化导致中脑边缘丧失 数据采集​​系统； (4) 使用PD实验模型来研究PD的调节 D3 受体，并找出抗帕金森药物最终失败的原因 上调该受体。这将进一步阐明 DAergic 的病理学 PD 特定临床症状的基础，并提供更广泛的基础 开发基于特定 DA 受体的有效治疗策略。