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: 7017056
• 负责人: JOHN D SALAMONE
• 金额: $ 13.37万
• 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/7017056
• 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）：帕金森病的症状，如运动障碍、运动迟缓和震颤，可由多巴胺（DA）神经元变性或服用DA拮抗剂引起。帕金森病的特点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。近年来，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起着重要作用。腺苷受体的几种亚型参与运动功能，解剖研究表明，腺苷A2A受体亚型在纹状体中表达程度相对较高。虽然几种类型的纹状体细胞含有一些腺嘌呤A2A受体，但这些受体在纹状体状神经元上的密度非常高，这些神经元也倾向于共同表达DA D2受体和脑啡肽。有人认为腺苷A2A受体拮抗剂可能作为抗帕金森病药物具有一些潜在的效用。在我们实验室最近的一项研究中，我们证明了腺苷A2A拮抗剂KF17837的IP注射也抑制了氟哌啶醇诱导的震颤颌运动，并逆转了这种D2拮抗剂诱导的运动抑制。在动物模型中，这种活性与腺苷A2A受体的拮抗作用可以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gaba能通路作为腺苷A2A拮抗剂抗帕金森病作用的可能介质的作用。这些拟进行的研究将集中在震颤颌运动模型，这与帕金森震颤有关。假设腺苷A2A拮抗剂作用于纹状体状gaba能神经元，这些神经元也表达DA D2受体。鉴于有研究表明氟哌啶醇增加苍白球细胞外GABA，且在苍白球注射双核碱可减少氟哌啶醇引起的震颤性下颚运动，我们假设，减少下颌运动活性的腺苷A2A拮抗剂剂量也会减少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以调节氟哌啶醇的行为和神经化学作用。这些假设将通过对作用于A2A受体的药物进行全身和腔内注射的研究来进行调查，并且提议的工作将涉及行为药理学和微透析方法的结合。这项研究旨在加强我们对震颤运动产生中涉及的神经递质相互作用的理解，并促进帕金森病治疗新药的开发。