SEROTONIN CONTROL MECHANISMS OF BASAL GANGLIA FUNCTION

描述：（逐字来自申请人的摘要） 和有效的治疗运动障碍，如帕金森氏病， 由于对基底神经节受体 系统适应多巴胺耗竭的后果。本研究着重 确定上调的5-羟色胺2A受体的作用，我们 假设提供了一种机制，使血清素对 多巴胺条件下的基底神经节传递和运动功能 耗尽我们的初步研究表明5-羟色胺2A的靶点 受体机制是直接纹状体黑质途径， 与GABA共定位的速激肽神经肽。新的实验 应用程序将测试中心假设：上调血清素2A 受体信号提供了5-羟色胺增强纹状体黑质的机制， 在多巴胺耗竭的条件下， 神经节功能和动物行为。在具体目标1中，我们将确定 上调5-羟色胺2A受体系统对 多巴胺耗竭纹状体内的5-羟色胺信号转导 测量血清素2A受体结合，其与磷酸肌醇的连接 水解、其对纹状体膜兴奋性的调节以及其能力 跨突触调节纹状体速激肽和GABA的表达。在 具体目标2，我们将确定速激肽纹状体黑质神经元是否对 在多巴胺耗竭的小鼠中， 通过增加黑质中的速激肽和GABA传递来抑制动物。 我们还将研究这种调节对运动行为的影响。 最后，在具体目标3中，我们将确定如何上调血清素2A 受体系统影响纹状体黑质系统调节 基底神经节多巴胺和GABA代谢，以及这些系统如何影响 多巴胺耗竭动物的行为恢复。获得的信息 这些研究将有助于更好地了解基底神经节 功能，并可能改变如何血清素途径被认为是当设计 治疗影响多巴胺传递的疾病的新药理学策略。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Attempts to develop new and effective treatments for movement disorders such as Parkinson's disease have been hampered by an insufficient knowledge of how basal ganglia receptor systems adapt to the consequences of dopamine depletion. This research focuses on determining the role of upregulated serotonin 2A receptors, which we hypothesize provide a mechanism for serotonin to exert greater control over basal ganglia transmission and locomotor function under conditions of dopamine depletion. Our preliminary studies indicate that the target of the serotonin 2A receptor mechanism is the DIRECT striatonigral pathway which utilizes tachykinin neuropeptides colocalized with GABA. New experiments of this application will test the central hypothesis that: upregulated serotonin 2A receptor signaling provides a mechanism for serotonin to enhance striatonigral transmission under conditions of dopamine depletion which influences basal ganglia function and animal behavior. In Specific Aim 1, we will determine the functional consequences of an upregulated serotonin 2A receptor system on serotonin signal transduction within the dopamine depleted striatum by measuring serotonin 2A receptor binding, its linkage to phosphoinositol hydrolysis, its modulation of striatal membrane excitability, and its ability to trans-synaptically regulate striatal tachykinin and GABA expression. In Specific Aim 2, we will determine if tachykinin striatonigral neurons react to the stimulation of upregulated serotonin 2A receptors in the dopamine depleted animal by increasing tachykinin and GABA transmission in the substantia nigra. We will also study the impact of this regulation on locomotor behavior. Finally, in Specific Aim 3, we will determine how an upregulated serotonin 2A receptor system influences the ability of the striatonigral system to regulate basal ganglia dopamine and GABA metabolism, and how these systems influence behavioral recovery of the dopamine depleted animal. Information obtained from these studies will contribute to a better understanding of basal ganglia function and may change how serotonin pathways are considered when designing new pharmacological strategies for diseases which affect dopamine transmission.