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: 6705647
• 负责人: JOHN D SALAMONE
• 金额: $ 12.46万
• 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/6705647
• 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，如运动迟缓和震颤，可由多巴胺(DA)神经元退化或DA拮抗剂药物治疗引起。帕金森病的特征是一系列神经化学事件，这些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、5-羟色胺、GABA和腺苷。在过去的几年里，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。腺苷受体的几个亚型参与运动功能，解剖学研究表明，腺苷A2A受体亚型在纹状体中的表达程度相对较高。虽然几种类型的纹状体细胞含有一些腺苷A2A受体，但这些受体在纹状体苍白质神经元上的密度很高，这些神经元也倾向于共同表达DA D2受体和脑啡肽。已有研究表明，腺苷A2a受体拮抗剂作为抗帕金森病药物具有一定的潜在应用价值。在我们实验室最近的一项研究中，已经证明IP注射腺苷A2A拮抗剂KF17837也能抑制氟哌啶醇引起的颌骨颤动，并逆转这种D2拮抗剂引起的运动抑制。这种活性与腺苷A2a受体拮抗可以在动物模型中导致抗帕金森效应的假设是一致的。本实验旨在研究纹状体蛋白GABA能通路作为腺苷A2a拮抗剂抗帕金森病作用的可能介体。这些拟议的研究将集中在与帕金森震颤相关的颤动下巴运动模型上。推测腺苷A2a拮抗剂作用于同样表达DA D2受体的纹状体苍白质GABA能神经元。鉴于有研究表明氟哌啶醇可增加苍白球细胞外GABA的释放，而注射荷包牡丹碱可减少氟哌啶醇引起的颌骨颤抖运动，故推测降低颌骨活动的腺苷A2A拮抗剂的剂量也将降低氟哌啶醇引起的苍白球GABA释放的增加。此外，假设腺苷激动剂和拮抗剂将相互作用来调节氟哌啶醇的行为和神经化学效应。这些假说将通过全身和纹状体内注射作用于A2A受体的药物的研究进行研究，拟议的工作将涉及行为药理学和微透析方法的组合。这项研究旨在加强我们对神经递质相互作用的了解，这些神经递质参与了颤动运动的产生，并促进了治疗帕金森症的新药的开发。