SEROTONIN CONTROL MECHANISMS OF BASAL GANGLIA FUNCTION

描述：(逐字摘自申请者的摘要)试图开发新的 以及对帕金森氏症等运动障碍的有效治疗 由于对基底神经节受体的了解不足 系统适应多巴胺耗尽的后果。本研究的重点是 在确定上调的5-羟色胺2A受体的作用方面，我们 假设提供了一种机制，使5-羟色胺更好地控制 多巴胺条件下的基底节传递和运动功能 耗尽。我们的初步研究表明，5-羟色胺2A的靶标 受体机制是直接纹状体黑质通路，它利用 速激肽神经肽与GABA共定位。这方面的新实验 应用程序将检验中心假设：上调5-羟色胺2A 受体信号为5-羟色胺增强纹状体黑质提供了一种机制 多巴胺耗竭条件下的传播影响基础 神经节功能和动物行为。在具体目标1中，我们将确定 5-羟色胺2A受体系统上调的功能影响 5-羟色胺在多巴胺耗竭纹状体内的信号转导 测定5-羟色胺2A受体结合及其与磷脂酰肌醇的联系 水解性及其对纹状体膜兴奋性的调节及其能力 跨突触调节纹状体速激肽和GABA的表达。在……里面 具体目标2，我们将确定速激肽纹状体黑质神经元是否对 多巴胺耗竭对5-羟色胺2A受体上调的刺激作用 通过增加速激肽和GABA在黑质的传递。 我们还将研究这一规定对运动行为的影响。 最后，在特定的目标3中，我们将确定上调的5-羟色胺2A是如何 受体系统影响纹状体黑质系统的调节能力 基底节多巴胺和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。获取的信息来自 这些研究将有助于更好地理解基底节。 并可能改变在设计时考虑5-羟色胺途径的方式 影响多巴胺传递的疾病的新药理策略。

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.