Electrochemical Analysis of Dopamine Release

多巴胺释放的电化学分析

• 批准号: 7415288
• 负责人: Margaret E Rice
• 金额: $ 42.25万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7415288
• 关键词: AMPA Receptors; Address; Affinity; Antioxidants; Axon; Behavior; Brain; Brain Diseases; CRSP3 gene; Cavia; Cell physiology; Cells; Characteristics; Cognitive; Condition; Corpus striatum structure; Data; Dendrites; Dependence; Detection; Diffuse; Disease; Dopamine; Dorsal; Elevation; Fire - disasters; Functional disorder; Funding; Generations; Glutamates; Goals; Hydrogen Peroxide; Ion Transport; Ions; Knockout Mice; Lead; Link; Mediating; Membrane Potentials; Metabolic; Methods; Midbrain structure; Mitochondria; Motor; N-Methyl-D-Aspartate Receptors; Neurons; Oxidative Stress; Pacemakers; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Population; Presynaptic Terminals; Production; Rate; Reactive Oxygen Species; Receptor Activation; Regulation; Relative (related person); Resistance; Rewards; Role; Schizophrenia; Signal Transduction; Slice; Structure; Substantia nigra structure; Testing; Tetrodotoxin; Therapeutic Intervention; Time; Ventral Striatum; Ventral Tegmental Area; Work; addiction; brain pathway; channel blockers; dopaminergic neuron; driving force; fluorescence imaging; gamma-Aminobutyric Acid; insight; mitochondrial membrane; neuronal cell body; pars compacta; prevent; research study; segregation; sulfonylurea receptor; transmission process

Dopamine (DA) is a key transmitter in motor, cognitive, and reward pathways of the brain, with dysfunction of DA transmission linked to significant disorders, including Parkinson's disease, schizophrenia, and addiction. The long-term goal of this project is to identify local factors that regulate somatodendritic DA release from DA neurons in the substantial nigra pars compacta (SNc) and ventral tegmental area (VTA) and axonal DA release in striatum. Our previous work focused on release regulation by endogenous glutamate, GABA, and Ca2+ entry, using real-time voltammetric recording of evoked DA release. We discovered that hydrogen peroxide (H202), a reactive oxygen species (ROS) is in intracellular messenger in SNc DA neurons, that both modulates cell firing rate and inhibits somatodendritic DA release. In dorsal striatum, H202 is a diffusible messenger that mediates regulation of axonal DA release by glutamate and GABA. These effects are mediated by H2O2-dependent activation of ATP-sensitive K+ (K-ATP) channels. Proposed work will provide mechanistic insight into regulation of DA transmission by H202, as well as indicate functional consequences of H2O2 signaling on somatodendritic and axonal DA release. Aim 1 will test the hypothesis that H2O2 activates K-ATP channels by decreasing channel sensitivity to ATP; Aim 2 will determine the ionic dependence of H2O2 generation; Aim 3 will investigate the role of H2O2 generation in reguaiton of somatodendritic DA release and DA cell physiology by glutamatergic NMDA receptors; and Aim 4 will evaluate the temporal and spatial characteristics of glutamate-dependent H202 signaling in dorsal striatum. Methods include voltammetric detection of DA release, whole-cell and excised patch recording, and fluorescence imaging of H2O2, intracellular ions, and mitochondria! potential, using transfected cells, isolated neurons, and brain slices from guinea pigs and K-ATP channel-subunit knockout mice. Several brain disorders that involve dopamine dysfunction, including Parkinson's disease and schizophrenia, have also been linked to oxidative stress. Proposed studies will clarify how endogenous hydrogen peroxide normally regulates dopamine release. Because unregulated H2O2 can lead to oxidative stress, however, the findings may also point to possible targets for therapeutic intervention in these disorders.

多巴胺 (DA) 是大脑运动、认知和奖赏通路中的关键递质，具有功能障碍 DA 传播与帕金森病、精神分裂症和成瘾等重大疾病有关。 该项目的长期目标是确定调节 DA 体细胞树突 DA 释放的局部因素 黑质致密部 (SNc) 和腹侧被盖区 (VTA) 以及轴突 DA 中的神经元 释放在纹状体中。我们之前的工作重点是内源性谷氨酸、GABA 和 Ca2+ 输入，使用诱发 DA 释放的实时伏安记录。我们发现氢 过氧化物 (H2O2) 是一种活性氧 (ROS)，存在于 SNc DA 神经元的细胞内信使中， 两者均可调节细胞放电率并抑制体细胞树突 DA 释放。在背侧纹状体中，H202 是 介导谷氨酸和 GABA 调节轴突 DA 释放的扩散信使。这些影响 由 H2O2 依赖性 ATP 敏感 K+ (K-ATP) 通道激活介导。拟议的工作将 提供 H202 对 DA 传输调节的机制见解，并表明功能 H2O2 信号传导对体细胞树突和轴突 DA 释放的影响。目标 1 将检验假设 H2O2 通过降低通道对 ATP 的敏感性来激活 K-ATP 通道；目标 2 将确定离子 H2O2 生成的依赖性；目标 3 将研究 H2O2 的产生在调节中的作用 谷氨酸能 NMDA 受体释放体细胞树突 DA 和 DA 细胞生理学；目标 4 将 评估背侧纹状体中谷氨酸依赖性 H202 信号传导的时间和空间特征。 方法包括伏安法检测 DA 释放、全细胞和切除的斑块记录，以及 H2O2、细胞内离子和线粒体的荧光成像！潜力，使用转染细胞， 从豚鼠和 K-ATP 通道亚基敲除小鼠中分离出神经元和脑切片。 几种涉及多巴胺功能障碍的脑部疾病，包括帕金森病和精神分裂症， 也与氧化应激有关。拟议的研究将阐明内源性过氧化氢如何 通常调节多巴胺的释放。然而，由于不受调节的 H2O2 会导致氧化应激 研究结果还可能指出这些疾病的治疗干预的可能目标。