Characterization of Cholinergic Modulation of Dopamine Neurotransmission

多巴胺神经传递的胆碱能调节的表征

• 批准号: 7935197
• 负责人: LESLIE A SOMBERS
• 金额: $ 18.11万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935197
• 关键词: Acetylcholine; Affect; Anesthesia procedures; Animals; Behavior; Brain; Carbachol; Chemical Agents; Chemicals; Choline; Cholinergic Agents; Crime; Cues; Data; Detection; Development; Dopamine; Drug abuse; Electrodes; Enzymes; Exhibits; Film; Glutamates; Goals; Health; Heterogeneity; Hydrogen Peroxide; Immobilized Enzymes; Individual; Investigation; Measurement; Mediating; Methods; Microelectrodes; Monitor; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurons; Nicotine; Nucleus Accumbens; Pathology; Pharmaceutical Preparations; Physiological; Play; Polymers; Productivity; Rattus; Regulation; Research; Resolution; Rewards; Role; Scanning; Self Administration; Site; Solid; Substance abuse problem; System; Techniques; Technology; Tegmentum Mesencephali; Time; United States; Ventral Tegmental Area; Work; addiction; awake; carbon fiber; cholinergic; cost; design; dopamine system; dopaminergic neuron; drug of abuse; in vivo; innovation; mesolimbic system; nerve supply; neurochemistry; neuronal cell body; neurotransmission; new technology; novel; oxidation; public health relevance; research study; sensor; stem; transmission process

DESCRIPTION (provided by applicant): The dopaminergic neurons of the mesolimbic dopamine (DA) system projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) are a common target for many drugs of abuse, and are thought to play a central role in the development of addiction. Recently, several studies have suggested that one endogenous neurochemical that serves to regulate these DA neurons is acetylcholine (ACh); however, direct evidence characterizing this modulation in intact animals is lacking, due largely to the absence of methods for monitoring in vivo ACh at sufficiently high spatial and temporal resolution. Thus, the studies described in this proposal are designed to characterize the cholinergic modulation of mesolimbic DA transmission by monitoring neurochemicals at both ends of this projection in separate experiments (that are not dependent on one another) using fast-scan cyclic voltammetry (FSCV) at carbon fiber microelectrodes. This electrochemical approach is well suited for real-time measurements of chemical changes in the brain, due to the excellent temporal and spatial resolution afforded by the technique. Electrochemical data will be analyzed with principal component regression, allowing individual chemical components to be objectively distinguished and selectively quantitated. The specific aims involve both the development of new technology (Aim 1) and innovative applications of existing analytical and neurobiological methods (Aim 2). They are: 1. The development and characterization of a novel electrochemical detection method for ACh that can be used to rapidly monitor fluctuations of this neurochemical in the VTA. 2. A quantitative study of how cholinergic compounds in the VTA modulate the temporal dynamics of dopamine efflux in the NAc of an awake animal. A better understanding of the cholinergic regulation of naturally occurring DA transmission may reveal a novel set of chemical mechanisms and physiological pathologies affecting the brain's reward system. PUBLIC HEALTH RELEVANCE: Drug abuse and addiction are significant problems in the United States. Estimates of the total overall costs of substance abuse in the United States-including health- and crime-related costs as well as losses in productivity-exceed half a trillion dollars annually. The dopaminergic neurons of the mesolimbic dopamine system projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) are a common target for many drugs of abuse, and are thought to play a central role in the development of addiction. The focus of this research is to understand how the endogenous neuromolecule acetylcholine can act at dopamine cell bodies to regulate dopamine release from the terminals. This work may reveal a novel set of chemical mechanisms and physiological pathologies affecting the brain's reward system.

描述（由申请人提供）：从腹侧细盖区域（VTA）到伏隔核（NAC）投射的中脱甲贝胺（DA）系统的多巴胺能神经元是许多滥用药物的常见靶标，并且被认为在成瘾的发展中起着中心作用。最近，一些研究表明，一种用于调节这些DA神经元的内源性神经化学是乙酰胆碱（ACH）。然而，缺乏表征完整动物这种调节的直接证据，这主要是由于缺乏在足够高的空间和时间分辨率下监测体内ACH的方法。因此，该提案中描述的研究旨在通过使用快速扫描的环状伏安仪（FSCV）在碳纤维纤维微电极上在单独的实验中（不依赖彼此依赖）在该投影两端的两端的神经化学物（不依赖彼此）中通过监测该投影两端的神经化学物的胆碱能调节。由于该技术提供了出色的时间和空间分辨率，这种电化学方法非常适合对大脑化学变化的实时测量。电化学数据将通过主要成分回归分析，从而使单个化学成分可以客观地区分和选择性地进行定量。具体目的涉及新技术的开发（AIM 1）和现有分析和神经生物学方法的创新应用（AIM 2）。它们是：1。用于ACH的新型电化学检测方法的发展和表征，可用于快速监测VTA中这种神经化学的波动。 2。关于VTA中胆碱能化合物如何调节多巴胺外排出的时间动力学的定量研究。对天然发生的DA传播的胆碱能调节的更好理解可能会揭示一组新型的化学机制和生理病理，从而影响大脑的奖励系统。 公共卫生相关性：药物滥用和成瘾是美国的重大问题。估计美国滥用药物滥用的总成本，包括与健康相关的和犯罪相关的成本，以及生产率超过半万亿美元的损失。从腹侧对接区域（VTA）到伏隔核（NAC）投射的中侧多巴胺系统的多巴胺能神经元是许多滥用药物的常见靶标，并且被认为在成瘾的发展中起着核心作用。这项研究的重点是了解内源性神经分子乙酰胆碱如何在多巴胺细胞体上起作用以调节末端多巴胺的释放。这项工作可能揭示了一套新颖的化学机制和生理病理，影响了大脑的奖励系统。

项目成果

Real-time chemical measurements of dopamine release in the brain.

• DOI: 10.1007/978-1-62703-251-3_16
• 发表时间: 2013-01-01
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Roberts, James G;Lugo-Morales, Leyda Z;Sombers, Leslie A
• 通讯作者: Sombers, Leslie A

NMDA Receptor-Dependent Cholinergic Modulation of Mesolimbic Dopamine Cell Bodies: Neurochemical and Behavioral Studies.

• DOI: 10.1021/acschemneuro.8b00492
• 发表时间: 2019-03-20
• 期刊: ACS chemical neuroscience
• 影响因子: 5
• 作者: Spanos M;Xie X;Gras-Najjar J;White SC;Sombers LA
• 通讯作者: Sombers LA

Enzyme-modified carbon-fiber microelectrode for the quantification of dynamic fluctuations of nonelectroactive analytes using fast-scan cyclic voltammetry.

• DOI: 10.1021/ac4017852
• 发表时间: 2013-09-17
• 期刊: ANALYTICAL CHEMISTRY
• 影响因子: 7.4
• 作者: Lugo-Morales, Leyda Z.;Loziuk, Philip L.;Corder, Amanda K.;Toups, J. Vincent;Roberts, James G.;McCaffrey, Katherine A.;Sombers, Leslie A.
• 通讯作者: Sombers, Leslie A.

Voltammetric detection of hydrogen peroxide at carbon fiber microelectrodes.

• DOI: 10.1021/ac100536s
• 发表时间: 2010-06-15
• 期刊: ANALYTICAL CHEMISTRY
• 影响因子: 7.4
• 作者: Sanford, Audrey L.;Morton, Stephen W.;Whitehouse, Kelsey L.;Oara, Hannah M.;Lugo-Morales, Leyda Z.;Roberts, James G.;Sombers, Leslie A.
• 通讯作者: Sombers, Leslie A.