Dopamine D2 and Adenosine A2A roles:Tremulous Movements

描述（由申请人提供）：帕金森综合征的症状，如运动不能、运动迟缓和震颤，可由多巴胺（DA）神经元变性或给予DA拮抗剂药物引起。帕金森症的特征在于反映基底神经节回路中几种神经递质之间相互作用的神经化学事件级联，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起着重要的作用。腺苷受体的几种亚型参与运动功能，解剖学研究表明腺苷A2 A受体亚型在纹状体内具有相对高的表达程度。尽管几种类型的纹状体细胞含有一些腺苷A2 A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，其也倾向于共表达DA D2受体和脑啡肽。已经表明腺苷A2 A受体的拮抗剂作为抗帕金森病药物可能具有一些潜在的效用。在我们实验室最近的一项研究中，证明了IP注射腺苷A2 A拮抗剂KF 17837也抑制了氟哌啶醇诱导的震颤性下颌运动，并逆转了这种D2拮抗剂诱导的运动抑制。这种活性特征与腺苷A2 A受体拮抗作用可导致动物模型中抗帕金森病作用的假设一致。拟进行的实验旨在研究纹状体苍白球GABA能通路作为腺苷A2 A拮抗剂的假定抗帕金森病作用的可能介质的作用。这些拟议的研究将集中在震颤下颌运动模型，这是相关的帕金森震颤。假设腺苷A2 A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。鉴于研究显示氟哌啶醇增加苍白球中的细胞外GABA，并且通过苍白球注射荷包牡丹碱减少氟哌啶醇诱导的震颤性颌运动，假设减少颌运动活动的腺苷A2 A拮抗剂的剂量也将减少氟哌啶醇诱导的苍白球中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。这些假设将使用涉及全身和纹状体内注射作用于A2 A受体的药物的研究进行调查，并且拟议的工作将涉及行为药理学和微透析方法的组合。这项研究旨在提高我们对震颤运动产生中所涉及的神经递质相互作用的理解，并促进治疗帕金森病的新药的开发。

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.