Regulation of Dopamine Release by ROS

ROS 对多巴胺释放的调节

• 批准号: 6579833
• 负责人: Margaret E Rice
• 金额: $ 20.02万
• 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 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6579833
• 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）是大脑运动和情绪通路的关键调节剂。前脑结构仅接收来自中脑 DA 神经元的 DA 输入，黑质致密部 (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伏核和其他边缘结构。两个系统中的 DA 细胞具有共同的生理特性，包括 DA 的体细胞树突释放。然而，一个显着的区别是，黑质纹状体 DA 细胞在帕金森病中退化，而中边缘 DA 细胞则幸免。一些生化差异可能导致 SNc 更脆弱，包括 SNc 中活性氧 (ROS) 的调节比 VTA 更弱。这种差异可能至关重要，因为氧化应激已被认为是帕金森病的致病因素。然而，除了具有潜在的神经毒性外，ROS 还可以充当信号剂。初步数据表明，一种 ROS，即过氧化氢 (H2O2)，可作为 DA 释放的调节剂。当外源应用时，H2O2 抑制 SNc 和 VTA 以及背侧纹状体和伏隔核中的释放。其他数据表明，局部刺激过程中产生的内源性 H2O2 会抑制 SNc 和纹状体中的 DA 释放，但不会抑制 VTA 中的 DA 释放。这些数据可能揭示黑质纹状体 DA 系统中的正常生理过程，如果 H2O2 的调节受到干扰，该过程可能会导致氧化应激。然而，尚不清楚 H2O2 本身是否是调节剂，或者它是否通过相关的 ROS 发挥作用。该 R21 提案的目标是确定参与调节黑质纹状体与中脑边缘 DA 系统中体细胞树突和突触 DA 释放的特定 ROS。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。 Aim t 中的实验将比较 SNc 和 VTA 中 ROS 对体细胞树突 DA 释放的调节，而 Aim 2 中的实验将比较背侧纹状体和伏隔核壳中的调节。令人惊讶的是，这里提出的研究将是首批研究脆弱和耐药 DA 系统之间 ROS 调节功能差异的研究之一。与 R21 计划的目标一致，这些数据应提供有关黑质纹状体变性的潜在机制的突破性新信息。