Extrastriatal functions of dopamine

多巴胺的纹状体外功能

• 批准号: 8070341
• 负责人: Thomas N Wichmann
• 金额: $ 37.73万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070341
• 关键词: Adverse effects; Affect; Agonist; American; Anatomy; Animals; Antiparkinson Agents; Basal Ganglia; Behavior; Behavioral; Biochemical; Cell Nucleus; Cells; Corpus striatum structure; Data; Dendrites; Development; Devices; Disease; Dopamine; Dopamine Agonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Dopaminergic Agents; Electrons; Event; Functional disorder; Gene Delivery; Generations; Globus Pallidus; Glutamates; Immunohistochemistry; Infusion procedures; Injection of therapeutic agent; Knowledge; Label; Lead; Ligands; Light; Link; Location; Measures; Methods; Microdialysis; Microinjections; Microscopic; Monkeys; Motor; Movement Disorders; Nerve Degeneration; Neurons; Parkinson Disease; Parkinsonian Disorders; Partner in relationship; Pathologic; Patients; Pattern; Pharmaceutical Preparations; Play; Prevalence; Primates; Receptor Activation; Relative (related person); Replacement Therapy; Resolution; Rodent; Role; Site; Structure of subthalamic nucleus; Substantia nigra structure; Symptoms; Synapses; Testing; Tyrosine 3-Monooxygenase; Work; base; behavior test; density; dopamine D5 receptor; dopaminergic neuron; expectation; extracellular; gamma-Aminobutyric Acid; in vivo; interest; nerve supply; neuronal cell body; neurosurgery; pars compacta; postsynaptic; presynaptic; public health relevance; receptor; research study; response; transmission process

DESCRIPTION (provided by applicant): There is accumulating evidence that dopamine loss at locations outside of the striatum such as the substantia nigra or the globus pallidus may play a significant role in the development of parkinsonism. Recent studies in animals, primarily rodents) have suggested that dopamine may also act at the level of the subthalamic nucleus (STN). In these animals, a direct dopaminergic projection from the substantia nigra pars compacta to the STN has been demonstrated. Furthermore, it appears that the activity of STN neurons is modulated through actions of dopamine at pre- and post-synaptic dopamine receptors in the STN, and that dopamine depletion in the STN leads to altered firing rates and more intense bursting in this nucleus. The extent and anatomy of the dopaminergic innervation of the STN, the function(s) of dopamine within the STN, and the effects of dopamine loss in the STN in the parkinsonian state have not been explored in primates. With the proposed studies, we will examine the anatomy and function of the dopamine supply to the STN in vivo in primates. With the experiments under aim 1, we will analyze the extent of the dopaminergic innervation and characterize the subcellular localization of dopamine receptors in the STN of normal and MPTP- treated (parkinsonian) monkeys, using a combination of light-microscopic and high resolution electron microscopic immunocytochemical methods. The experiments under aim 2 will study the functional effects of dopaminergic compounds, locally administered in the STN, on the activity of STN neurons in normal and parkinsonian monkeys. We will examine the effects of dopamine receptor agonists and antagonists, injected locally into the STN with a microinjection/recording device. In addition, microdialysis experiments will be carried out to measure the presynaptic effects of dopamine on GABA release in the STN, as well as electrophysiological recordings in the primary targets of STN projections, i.e., the external and internal pallidal segments. Finally, under aim 3, we will study the behavioral effects of dopamine receptor blockade in the STN in normal animals, and activation of dopamine receptors in the STN in parkinsonism, with the expectation that disruption of dopaminergic transmission contributes to parkinsonism, and replacement of dopaminergic function in the parkinsonian state may ameliorate parkinsonian symptoms. Taken together, these studies will provide us with a thorough examination of dopaminergic functions in the primate STN, will help us to understand further the effects of dopamine loss at this extrastriatal site, and may identify the STN as a target for focal dopamine replacement strategies in parkinsonism, such as gene delivery methods or grafting. PUBLIC HEALTH RELEVANCE: The neuronal activity in the subthalamic nucleus is strongly affected by the dopamine depletion in the basal ganglia that occurs in Parkinson's disease, making this nucleus the primary targets of functional neurosurgery to treat parkinsonism. Activity changes in the subthalamic nucleus are usually seen as secondary events, triggered by striatal dopamine loss. However, there is accumulating evidence that dopamine loss within the subthalamic nucleus also contributes to the neuronal activity changes, and to the generation of parkinsonism. We will explore this hypothesis in parkinsonian primates through anatomical, electrophysiologic, biochemical and behavioral experiments. These studies will expand our knowledge of the pathophysiology of parkinsonism, and may identify the subthalamic nucleus as a location at which current dopaminergic therapies work. If significant dopaminergic effects are seen in the subthalamic nucleus, it may emerge as a new target for highly specific local dopamine replacement therapies for parkinsonian patients.

描述（由申请人提供）：越来越多的证据表明，纹状体以外部位（例如黑质或苍白球）的多巴胺损失可能在帕金森病的发展中发挥重要作用。最近对动物（主要是啮齿动物）的研究表明，多巴胺也可能在丘脑底核（STN）水平发挥作用。在这些动物中，已证实从黑质致密部到 STN 的直接多巴胺能投射。此外，STN 神经元的活动似乎是通过 STN 中突触前和突触后多巴胺受体的多巴胺作用来调节的，并且 STN 中的多巴胺耗竭导致该核中的放电率改变和更强烈的爆发。 STN 多巴胺能神经支配的程度和解剖结构、STN 内多巴胺的功能以及帕金森状态下 STN 中多巴胺损失的影响尚未在灵长类动物中进行过探索。通过拟议的研究，我们将检查灵长类动物体内 STN 多巴胺供应的解剖结构和功能。通过目标 1 下的实验，我们将结合光学显微镜和高分辨率电子显微镜免疫细胞化学方法，分析多巴胺能神经支配的程度，并表征正常和 MPTP 治疗（帕金森病）猴子 STN 中多巴胺受体的亚细胞定位。目标 2 下的实验将研究在 STN 中局部施用的多巴胺能化合物对正常和帕金森猴 STN 神经元活性的功能影响。我们将检查用显微注射/记录装置局部注射到 STN 中的多巴胺受体激动剂和拮抗剂的作用。此外，还将进行微透析实验，以测量多巴胺对 STN 中 GABA 释放的突触前影响，以及 STN 投射的主要目标（即外部和内部苍白球节段）的电生理记录。最后，在目标 3 下，我们将研究正常动物 STN 中多巴胺受体阻断的行为效应，以及帕金森症中 STN 中多巴胺受体的激活，期望多巴胺能传递的破坏有助于帕金森症，而帕金森状态下多巴胺能功能的替代可能会改善帕金森症症状。总而言之，这些研究将为我们提供对灵长类 STN 中多巴胺能功能的彻底检查，将帮助我们进一步了解多巴胺损失在该纹状体外部位的影响，并可能将 STN 确定为帕金森病局灶性多巴胺替代策略的目标，例如基因递送方法或移植。 公共健康相关性：丘脑底核中的神经元活动受到帕金森病中基底神经节多巴胺消耗的强烈影响，使得该核成为功能性神经外科治疗帕金森病的主要目标。丘脑底核的活动变化通常被视为继发事件，由纹状体多巴胺损失引发。然而，越来越多的证据表明，丘脑底核内多巴胺的丢失也会导致神经元活动的变化，并导致帕金森症的产生。我们将通过解剖学、电生理学、生化和行为实验在帕金森灵长类动物中探索这一假设。这些研究将扩大我们对帕金森病病理生理学的了解，并可能确定丘脑底核是当前多巴胺能疗法发挥作用的部位。如果在丘脑底核中观察到显着的多巴胺能效应，那么它可能会成为帕金森病患者高度特异性局部多巴胺替代疗法的新靶点。