Dopamine D2 and Adenosine A2A roles:Tremulous Movements

多巴胺 D2 和腺苷 A2A 作用：颤抖运动

• 批准号: 6831712
• 负责人: JOHN D SALAMONE
• 金额: $ 13.69万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831712
• 关键词: Parkinson' s disease; adenosine; antiparkinson drugs; basal ganglia; behavior test; corpus striatum; dopamine; drug design /synthesis /production; electrochemistry; gamma aminobutyrate; haloperidol; high performance liquid chromatography; jaw movement; laboratory rat; lenticular nucleus; microdialysis; neural degeneration; neurochemistry; neurotransmitter antagonist; neurotransmitter receptor; statistics /biometry; tremor

DESCRIPTION (provided by applicant): Symptoms of parkinsonism, such as akinesia, bradykinesia, and tremor, can be caused by degeneration of dopamine (DA) neurons, or by administration of DA antagonist drugs. Parkinsonism is characterized by a cascade of neurochemical events that reflect interactions between several neurotransmitters in the circuitry of the basal ganglia, including DA, acetylcholine, serotonin, GABA and adenosine. Within the last few years, increasing evidence has accumulated indicating that central adenosine neurons play an important role in modulating the functional circuitry of the basal ganglia. Several subtypes of adenosine receptors are involved in motor function, and anatomical studies have demonstrated that the adensonine A2A receptor subtype has a relatively high degree of expression within the striatum. Although several types of striatal cells contain some adensonine A2A receptors, these receptors are present in very high densities on striatopallidal neurons, which also tend to co-express DA D2 receptors and enkephalin. It has been suggested that antagonists of adenosine A2A receptors could have some potential utility as antiparkinsonian drugs. In a recent study from our laboratory, it was demonstrated that IP injections of the adenosine A2A antagonist, KF17837, also suppressed haloperidol-induced tremulous jaw movements, and reversed the locomotor suppression induced by this D2 antagonist. This profile of activity is consistent with the hypothesis that antagonism of adenosine A2A receptors can result in antiparkinsonian effects in animal models. The proposed experiments are designed to investigate the role of the striatopallidal GABAergic pathway as a possible mediator of the putative antiparkinsonian effects of adenosine A2A antagonists. These proposed studies will focus on the tremulous jaw movement model, which is related to parkinsonian tremor. It is hypothesized that adenosine A2A antagonists are acting on striatopallidal GABAergic neurons that also express DA D2 receptors. In view of research showing that haloperidol increases extracellular GABA in globus pallidus, and that haloperidol-induced tremulous jaw movements are reduced by pallidal injections of bicuculline, it is hypothesized that doses of adenosine A2A antagonists that reduce jaw movement activity also will reduce haloperidol-induced increases in GABA release in globus pallidus. In addition, it is hypothesized that adenosine agonists and antagonists will interact to regulate the behavioral and neurochemical effects of haloperidol. These hypotheses will be investigated using studies that involve both systemic and intrastriatal injections of drugs that act upon A2A receptors, and the proposed work will involve a combination of behavioral pharmacology and microdialysis methods. This research is designed to enhance our understanding of the neurotransmitter interactions that are involved in the generation of tremulous movements, and to foster the development of new drugs for the treatment of parkinsonism.

描述（由申请人提供）：帕金森症的症状，例如运动不能、运动迟缓和震颤，可能是由多巴胺（DA）神经元变性或施用DA拮抗剂药物引起的。帕金森病的特征是一系列神经化学事件，反映了基底神经节回路中几种神经递质之间的相互作用，包括 DA、乙酰胆碱、血清素、GABA 和腺苷。在过去的几年中，越来越多的证据表明中央腺苷神经元在调节基底神经节的功能回路中发挥着重要作用。腺苷受体的几种亚型与运动功能有关，解剖学研究表明，腺苷A2A受体亚型在纹状体内有相对较高程度的表达。尽管几种类型的纹状体细胞含有一些腺苷酸 A2A 受体，但这些受体以非常高的密度存在于纹状体苍白球神经元上，这些神经元也倾向于共表达 DA D2 受体和脑啡肽。有人建议，腺苷 A2A 受体拮抗剂可能具有作为抗帕金森病药物的一些潜在用途。我们实验室最近的一项研究表明，腹腔注射腺苷 A2A 拮抗剂 KF17837 也能抑制氟哌啶醇引起的下颌运动，并逆转这种 D2 拮抗剂引起的运动抑制。这种活性特征与腺苷 A2A 受体的拮抗作用可在动物模型中产生抗帕金森病作用的假设是一致的。所提出的实验旨在研究纹状体苍白球 GABA 能通路作为腺苷 A2A 拮抗剂的推定抗帕金森病作用的可能介质的作用。这些拟议的研究将重点关注与帕金森病震颤相关的震颤下颌运动模型。据推测，腺苷 A2A 拮抗剂作用于也表达 DA D2 受体的纹状体苍白球 GABA 能神经元。鉴于研究表明，氟哌啶醇增加了苍白球中的细胞外 GABA，并且苍白球注射荷包牡丹碱可以减少氟哌啶醇引起的震颤下颌运动，因此推测，减少下颌运动活动的腺苷 A2A 拮抗剂剂量也将减少氟哌啶醇引起的苍白球中 GABA 释放的增加。此外，据推测，腺苷激动剂和拮抗剂会相互作用来调节氟哌啶醇的行为和神经化学作用。这些假设将通过涉及全身和纹状体内注射作用于 A2A 受体的药物的研究来进行调查，并且拟议的工作将涉及行为药理学和微透析方法的结合。这项研究旨在增强我们对参与颤抖运动产生的神经递质相互作用的理解，并促进治疗帕金森病的新药物的开发。