Regulation of Dopamine Release by ROS

ROS 对多巴胺释放的调节

• 批准号: 6683194
• 负责人: Margaret E Rice
• 金额: $ 20.07万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6683194
• 关键词: corpus striatum; dendrites; dopamine; free radical oxygen; guinea pigs; high performance liquid chromatography; hydrogen peroxide; hydroxyl radical; microelectrodes; neurochemistry; neuroregulation; neurotransmitter transport; nucleus accumbens; substantia nigra; superoxides; synapses; tegmentum; tissue /cell preparation; voltage /patch clamp

DESCRIPTION (provided by applicant): Dopamine (DA) is a key modulator of motor and emotive pathways in the brain. Forebrain structures receive DA input exclusively from midbrain DA neurons, with cells of the substantia nigra pars compacta (SNc) projecting via the nigrostriatal pathway to dorsal striatum and those of the adjacent ventral tegmental area (VTA) project via the mesolimbic pathway to nucleus accumbens and other limbic structures. DA cells in both systems share common physiological properties, including somatodendritic release of DA. A significant difference, however, is that nigrostriatal DA cells degenerate in Parkinson's disease, whereas mesolimbic DA cells are spared. Several biochemical differences may contribute to greater SNc vulnerability, including weaker regulation of reactive oxygen species (ROS) in SNc than in VTA. This difference may be crucial, because oxidative stress has been proposed as a causal factor in Parkinson's disease. In addition to being potentially neurotoxic, however, ROS can act as signaling agents. Preliminary data implicate one ROS, hydrogen peroxide (H202), as a modulator of DA release. When applied exogenously, H202 inhibits release in the SNc and VTA as well as in dorsal striatum and nucleus accumbens. Additional data suggest that endogenous H202 generated during local stimulation inhibits DA release in the SNc and striatum, but not in the VTA. These data may reveal a normal physiological process in the nigrostriatal DA system that could contribute to oxidative stress, if regulation of H202 became disrupted. It is not clear, however, whether H202 per se is the modulator or whether it acts via related ROS. The goal of this R21 proposal is to determine specific ROS involved in modulating somatodendritic and synaptic DA release in the nigrostriatal vs. mesolimbic DA systems. Evoked DA release will be monitored using evoked using carbon-fiber microelectrodes and fast-scan cyclic voltammetry. Experiments in Aim t will compare regulation of somatodendritic DA release by ROS in the SNc and VTA, whereas those in Aim 2 will compare regulation in the dorsal striatum and the shell of the nucleus accumbens. Surprisingly, the studies proposed here would be among the first to investigate functional differences in ROS regulation between vulnerable and resistant DA systems. Consistent with the goals of the R21 program, these data should provide ground-breaking new information about underlying mechanisms in nigrostriatal degeneration.

描述（由申请人提供）：多巴胺（DA）是大脑中运动和情绪通路的关键调节剂。前脑结构仅接受来自中脑DA神经元的DA输入，黑质黑部（SNc）的细胞通过黑质纹状体通路投射到背侧纹状体，而邻近的腹侧被盖区（VTA）的细胞通过中脑边缘通路投射到中脑背侧核和其他边缘结构。DA细胞在这两个系统中有着共同的生理特性，包括体树突释放DA。然而，一个显着的差异是，黑质纹状体DA细胞退化帕金森氏病，而中脑边缘DA细胞幸免。几个生化差异可能有助于更大的SNc的脆弱性，包括较弱的调节活性氧（ROS）在SNc比VTA。这种差异可能是至关重要的，因为氧化应激已被认为是帕金森病的一个致病因素。然而，除了具有潜在的神经毒性外，ROS还可以作为信号传导剂。初步数据暗示一种ROS，过氧化氢（H2O2），作为DA释放的调节剂。当外源性应用时，H2O2抑制SNc和VTA以及背侧纹状体和背侧核中的释放。另外的数据表明，在局部刺激期间产生的内源性H2O2抑制SNc和纹状体中的DA释放，但不抑制VTA中的DA释放。这些数据可能揭示了黑质纹状体DA系统中的正常生理过程，如果H2O2的调节被破坏，则可能导致氧化应激。然而，尚不清楚H2O2本身是否是调节剂或其是否通过相关的ROS起作用。这个R21建议的目标是确定特定的活性氧参与调节体树突和突触DA释放在黑质纹状体与中脑边缘DA系统。将使用碳纤维微电极和快速扫描循环伏安法来监测诱发的DA释放。目标t中的实验将比较SNc和VTA中ROS对体树突DA释放的调节，而目标2中的实验将比较背侧纹状体和背侧核壳中的调节。令人惊讶的是，这里提出的研究将是第一个调查脆弱和耐药DA系统之间ROS调节的功能差异。与R21计划的目标一致，这些数据应该提供有关黑质纹状体变性潜在机制的突破性新信息。