Characterization of Cholinergic Modulation of Dopamine Neurotransmission

多巴胺神经传递的胆碱能调节的表征

基本信息

批准号：
7773610
负责人：
LESLIE A SOMBERS
金额：
$ 17.81万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7773610
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

项目摘要

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）：从腹侧被盖区（VTA）投射到伏隔核（NAc）的中脑边缘多巴胺（DA）系统的多巴胺能神经元是许多滥用药物的共同目标，并且被认为发挥着重要作用。在成瘾的发展中发挥着核心作用。最近，一些研究表明，乙酰胆碱 (ACh) 是一种调节这些 DA 神经元的内源性神经化学物质。然而，缺乏表征完整动物中这种调节的直接证据，这主要是由于缺乏以足够高的空间和时间分辨率监测体内乙酰胆碱的方法。因此，本提案中描述的研究旨在通过在单独的实验（彼此不依赖）中使用快速扫描循环伏安法（FSCV）监测该投射两端的神经化学物质来表征中脑边缘DA传输的胆碱能调节。碳纤维微电极。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实时测量大脑中的化学变化。电化学数据将通过主成分回归进行分析，从而能够客观地区分和选择性定量各个化学成分。具体目标涉及新技术的开发（目标 1）和现有分析和神经生物学方法的创新应用（目标 2）。它们是： 1. 一种新型乙酰胆碱电化学检测方法的开发和表征，可用于快速监测 VTA 中这种神经化学物质的波动。 2. 定量研究 VTA 中的胆碱能化合物如何调节清醒动物 NAc 中多巴胺流出的时间动态。更好地了解自然发生的 DA 传输的胆碱能调节可能会揭示影响大脑奖励系统的一组新的化学机制和生理病理学。公共卫生相关性：药物滥用和成瘾是美国的重大问题。据估计，美国药物滥用造成的总成本（包括健康和犯罪相关成本以及生产力损失）每年超过 5000 亿美元。从腹侧被盖区（VTA）投射到伏核（NAc）的中脑边缘多巴胺系统的多巴胺能神经元是许多药物滥用的常见目标，并且被认为在成瘾的发展中发挥着核心作用。这项研究的重点是了解内源性神经分子乙酰胆碱如何作用于多巴胺细胞体，从而调节末梢的多巴胺释放。这项工作可能揭示了一套影响大脑奖励系统的新颖的化学机制和生理病理学。