Dopamine Release Regulation by Co-Released Glutamate and GABA

谷氨酸和 GABA 共同释放的多巴胺释放调节

• 批准号: 9031754
• 负责人: Margaret E Rice
• 金额: $ 39.85万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031754
• 关键词: AMPA Receptors; Acute; Address; Axon; Behavior; Brain; Breeding; Case Study; Cells; Cocaine; Cognition; Companions; Corpus striatum structure; Coupled; Data; Disease; Dopamine; Dopamine D2 Receptor; Dorsal; Food; Functional disorder; GABA Receptor; Glutamate Receptor; Glutamates; Goals; Health; Homeostasis; Immunoelectron Microscopy; Injection of therapeutic agent; Interneurons; Learning; Mediating; Midbrain structure; Monitor; Motivation; Movement; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; Neurotransmitters; Nucleus Accumbens; Output; Parkinson Disease; Pathway interactions; Pattern; Pharmaceutical Preparations; Play; Preparation; Process; Prosencephalon; Regulation; Reporting; Rewards; Role; Scanning; Signal Transduction; Slice; Source; Stimulus; Structure; Substantia nigra structure; Testing; Therapeutic Intervention; Translating; Ventral Striatum; Ventral Tegmental Area; addiction; base; cholinergic; cocaine exposure; dopaminergic neuron; driving behavior; extracellular; gamma-Aminobutyric Acid; in vivo; mesolimbic system; motivated behavior; motor deficit; motor learning; neuropsychiatric disorder; novel; novel strategies; optogenetics; pars compacta; postsynaptic; psychostimulant; putamen; receptor; response; transmission process; voltage clamp

DESCRIPTION (provided by applicant): The transmitter dopamine (DA) is critical for motivation, reward, movement, and cognition. Originating in the ventral tegmental area (VTA), the mesolimbic DA pathway projects to the nucleus accumbens (NAc) core and shell where DA transmission contributes to the rewarding effects of food and drugs, and promotes goal- directed behavior and reward-related learning. Operating in parallel with the mesolimbic system, the nigrostriatal DA pathway originates in the substantia nigra pars compacta (SNc) and projects to the caudate- putamen (CPu). This pathway contributes to motivated behavior and movement, and is involved in driving behaviors that have transitioned from goal-directed and intentional to automatic and compulsive. Given the key roles of these pathways, dysfunction of DA transmission plays a key role in neuropsychiatric disorders including addiction to psychostimulant drugs and the motor deficits of Parkinson's disease. Elucidating causal factors in these disorders, and developing corresponding treatments, requires an understanding of factors that govern DA release. It is often assumed that DA signaling is governed solely by DA neuron firing rate and pattern, with homogeneous activity-dependent changes in extracellular DA concentration ([DA]o) throughout the striatum. However, this is not the case: studies using fast-scan cyclic voltammetry (FCV) show that DA release is regulated locally within the striatum, with temporally and spatially discrete [DA]o transients detected in vivo and in ex vivo brain slices. Preliminary data suggest that a novel source of dynamic local DA release regulation is mediated by glutamate and GABA that are co-released from striatal DA axons. This project will determine autoregulatory roles of co-released glutamate and GABA on axonal DA release in NAc (Aim 1) and CPu (Aim 2), and somatodendritic DA release in VTA and SNc (Aim 3), in ex vivo slices from mice that express channelrhodopsin 2 (ChR2) in DA neurons. Companion studies will assess the presence of glutamate and GABA receptor subunits on striatal DA axons using immuno-electron microscopy. Based on preliminary data showing enhanced AMPA receptor-dependent regulation of striatal DA release in ex vivo slices 24 h after a single cocaine injection, each aim will include examination of the effect of acute cocaine exposure on DA release regulation by co-released transmitters. Overall, this project will define the roles of co-released glutamate and GABA in sculpting how changes in DA neuron activity translate into DA release, and how this regulation can be disrupted by cocaine.

描述（由申请人提供）：发射机多巴胺（DA）对于动机，奖励，运动和认知至关重要。源自腹侧对段区域（VTA），中唇DA途径向伏隔核（NAC）核心和外壳投射出DA传播有助于食品和药物的奖励作用，并促进目标行为和奖励相关的学习。黑质纹状体DA途径与中边系统并行运行，起源于Nigra pars compacta（SNC），并向Caudate-ptamen（CPU）进行项目。该途径有助于动机的行为和运动，并参与了从目标定向和故意转变为自动和强迫性的驱动行为。鉴于这些途径的关键作用，DA传播功能障碍在神经精神疾病中起关键作用，包括对精神刺激药物成瘾和帕金森氏病的运动不足。阐明这些疾病中的因果因素并开发相应的治疗方法需要了解控制DA释放的因素。通常认为DA信号传导仅受DA神经元的发射速率和模式的控制，并且整个纹状体的细胞外DA浓度（[DA] O）的均匀活性依赖性变化。然而，情况并非如此：使用快速扫描环状伏安法（FCV）的研究表明，DA释放在纹状体内受到局部调节，在体内和离体脑切片中，在时间和空间上进行了暂时和空间离散的[dA] o瞬变。初步数据表明，动态局部DA释放调节的新来源是由谷氨酸和GABA介导的，这些释放是从纹状体DA轴突共同发出的。该项目将确定NAC（AIM 1）和CPU（AIM 2）和VTA和SNC中的somatdendritic da释放（AIM 3）（AIM 3）的共释放的谷氨酸和GABA在轴突DA释放中的自动调节作用（AIM 2）（AIM 3），在体外切片中，来自小鼠的小鼠，这些小鼠在DA Neuron中表达ChannelRhodopsin 2（Chr2）的小鼠。伴侣研究将使用免疫电子显微镜评估纹状体DA轴突上谷氨酸和GABA受体亚基的存在。基于单个可卡因注射后24小时24小时，基于提高AMPA受体依赖性调节的AMPA受体依赖性调节，每个目标都包括检查急性可卡因暴露对共同发行的发射器对DA释放调控的影响。总体而言，该项目将定义共同发行的谷氨酸和GABA在雕刻DA神经元活动的变化如何转化为DA释放的作用，以及如何通过可卡因破坏这种调节。