Electrochemical Analysis of Dendritic Dopamine Release

树突状多巴胺释放的电化学分析

• 批准号: 6740204
• 负责人: Margaret E Rice
• 金额: $ 32.11万
• 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 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6740204
• 关键词: GABA receptor; calcium flux; cell cell interaction; central neural pathway /tract; dendrites; dopamine; dopamine receptor; electrochemistry; electrophysiology; glutamate receptor; guinea pigs; histology; hydrogen peroxide; membrane potentials; microelectrodes; neural transmission; neurotransmitter transport; substantia nigra

DESCRIPTION (provided by applicant): Dopamine (DA) is a key transmitter in motor and emotive pathways of the brain. Dysfunction of dopaminergic neurotransmission underlies a variety of brain disorders that have a critical impact on society, including Parkinson's and Huntington's diseases, schizophrenia, and addiction. DA cell groups in the midbrain provide the primary source of DA to the CNS. Cells of the substantia nigra pars compacta (SNc) project rostrally to innervate the dorsal striatum (nigrostriatal DA system) whereas those of the adjacent ventral tegmental area (VTA) project to the nucleus accumbens and other limbic structures (mesolimbic DA system). A potentially unique characteristic of DA neurons is that they release DA from their dendrites in midbrain, as well as from distant axon terminals. Dendritic, as well as terminal release of DA is critical for DA-mediated behaviors, yet little is known about factors that regulate DA release In midbrain. Using carbon-fiber microelectrodes and fast-scan cyclic voltammetry to detect evoked DA release in real-time in brain slices, we have found significant differences in the Ca2+-dependence and Ca2+-channels required for dendritic vs. terminal release. Further, we have found distinct patterns of regulation by glutamate and GABA acting at ionotropic receptors in SNc, VTA and striatum. Significantly, we also discovered a novel, endogenous regulator of the nigrostriatal DA release: the reactive oxygen species (ROS), H202. In this continuation, we will investigate the distinct Ca2+ dependence of dendritic DA release, with emphasis on contributions from synaptic input to DA cells and release of Ca2+ from intracellular stores (Aim I). We will also elucidate the role of ROS as modulators of dendritic and terminal DA overflow (Aim ll-IV). Aim II will examine the involvement of H202 and other ROS in nigrostriatal vs. mesolimbic DA systems. Aim Ill will investigate sources of ROS, including terminals and cells adjacent to DA release sites. Aim IV will test whether H202 inhibits dendritic DA overflow by causing hyperpolarization of DA cells; effects on membrane properties will be indicated by whole cell recording.

描述（由申请人提供）：多巴胺（DA）是大脑运动和情感途径中的关键发射器。多巴胺能神经传递的功能障碍是各种脑部疾病对社会产生关键影响的脑部疾病，包括帕金森氏症和亨廷顿疾病，精神分裂症和成瘾。中脑中的DA细胞组为CNS提供了DA的主要来源。黑质nigra pars comcacta（SNC）的细胞可扣除背侧纹状体（黑质纹状体DA系统），而相邻的腹侧偏段面积（VTA）的细胞向伏隔核和其他边缘结构（Mesolimbic DA系统）进行了邻近的腹侧段面积（VTA）项目。 DA神经元的潜在独特特征是，它们从中脑的树突以及远处的轴突末端释放了DA。树突状以及DA的末端释放对于DA介导的行为至关重要，但对调节中脑释放的因素知之甚少。使用碳纤维微电极和快速扫描的循环伏安法以实时检测诱发的DA释放，在脑切片中，我们发现了CA2+依赖性和树突状的Ca2+依赖性和CA2+通道的显着差异。此外，我们发现了在SNC，VTA和纹状体中作用于谷氨酸和GABA作用的不同调节模式。值得注意的是，我们还发现了一个新型的，内源性的调节剂，是骨纹状体释放的：活性氧（ROS），H202。在此延续中，我们将研究树突DA释放的不同Ca2+依赖性，重点是从突触输入到DA细胞的贡献以及从细胞内存储中释放Ca2+的贡献（AIM I）。我们还将阐明ROS作为树突状和末端DA溢出的调节剂的作用（AIM LL-IV）。 AIM II将研究H202和其他ROS在鼻纹和中脑脱脂DA系统中的参与。 AIM ILL将研究ROS的来源，包括末端和与DA释放位点相邻的细胞。 AIM IV将测试H202是否通过导致DA细胞超极化来抑制树突DA溢出；全细胞记录将表明对膜特性的影响。