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

基本信息

  • 批准号:
    9031754
  • 负责人:
  • 金额:
    $ 39.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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(申请人提供):递质多巴胺(DA)对动机、奖励、运动和认知至关重要。中脑边缘DA通路起源于腹侧被盖区(VTA),投射到伏隔核(NAC)的核心和外壳,在那里DA传递有助于食物和药物的奖赏效应,并促进目标定向行为和奖赏相关学习。黑质纹状体DA通路与中脑边缘系统平行,起源于黑质致密部(SNC),投射至尾壳核(CPU)。这条途径促进了动机行为和运动,并参与了从目标导向和故意到自动和强制的驾驶行为。鉴于这些通路的关键作用,DA传递功能障碍在神经精神障碍中起着关键作用,包括对精神刺激性药物的上瘾和帕金森病的运动障碍。阐明这些疾病的病因,并开发相应的治疗方法,需要了解控制DA释放的因素。人们通常认为DA信号仅受DA神经元的放电频率和模式控制,纹状体细胞外DA浓度([DA]o)具有均匀的活动依赖性变化。然而,情况并非如此:使用快速扫描循环伏安法(FCV)的研究表明,DA的释放在纹状体内受到局部调节,在体内和体外脑片中检测到时间和空间离散的[DA]o瞬变。初步数据表明,纹状体DA轴突共同释放的谷氨酸和GABA介导了一种新的动态局部DA释放调节来源。本项目将确定共同释放的谷氨酸和GABA对NAc(Aim 1)和CPU(Aim 2)轴突DA释放以及VTA和SNC(Aim 3)躯体树突状DA释放的自我调节作用,来自DA神经元表达通道视紫红质2(ChR2)的小鼠的体外切片。配套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受体亚单位的存在。根据初步数据显示,单次注射可卡因24小时后,AMPA受体对纹状体脑片DA释放的调节增强,每个目的都包括研究急性可卡因暴露对共同释放的递质调节DA释放的影响。总体而言,这个项目将定义共同释放的谷氨酸和GABA在塑造DA神经元活动的变化如何转化为DA释放的过程中的作用,以及这种调节如何被可卡因扰乱。

项目成果

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Margaret E Rice其他文献

Margaret E Rice的其他文献

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{{ truncateString('Margaret E Rice', 18)}}的其他基金

Afterhyperpolarization in dopamine neurons, H2O2 and KATP channels
多巴胺神经元、H2O2 和 KATP 通道的后超极化
  • 批准号:
    7921292
  • 财政年份:
    2008
  • 资助金额:
    $ 39.85万
  • 项目类别:
Regulation of Dopamine Release by ROS
ROS 对多巴胺释放的调节
  • 批准号:
    6683194
  • 财政年份:
    2002
  • 资助金额:
    $ 39.85万
  • 项目类别:
Regulation of Dopamine Release by ROS
ROS 对多巴胺释放的调节
  • 批准号:
    6579833
  • 财政年份:
    2002
  • 资助金额:
    $ 39.85万
  • 项目类别:
ASCORBATE AND GLUTATHIONE IN CNS INJURY
抗坏血酸和谷胱甘肽在中枢神经系统损伤中的作用
  • 批准号:
    6336719
  • 财政年份:
    2000
  • 资助金额:
    $ 39.85万
  • 项目类别:
ASCORBATE AND GLUTATHIONE IN CNS INJURY
抗坏血酸和谷胱甘肽在中枢神经系统损伤中的作用
  • 批准号:
    6205052
  • 财政年份:
    1999
  • 资助金额:
    $ 39.85万
  • 项目类别:
ASCORBATE AND GLUTATHIONE IN CNS INJURY
抗坏血酸和谷胱甘肽在中枢神经系统损伤中的作用
  • 批准号:
    6112550
  • 财政年份:
    1998
  • 资助金额:
    $ 39.85万
  • 项目类别:
ASCORBATE AND GLUTATHIONE IN CNS INJURY
抗坏血酸和谷胱甘肽在中枢神经系统损伤中的作用
  • 批准号:
    6243843
  • 财政年份:
    1997
  • 资助金额:
    $ 39.85万
  • 项目类别:
Electrochemical Analysis of Dopamine Release
多巴胺释放的电化学分析
  • 批准号:
    8132779
  • 财政年份:
    1997
  • 资助金额:
    $ 39.85万
  • 项目类别:
Electrochemical Analysis of Dendritic Dopamine Release
树突状多巴胺释放的电化学分析
  • 批准号:
    6740204
  • 财政年份:
    1997
  • 资助金额:
    $ 39.85万
  • 项目类别:
Electrochemical Analysis of Dendritic Dopamine Release
树突状多巴胺释放的电化学分析
  • 批准号:
    7051463
  • 财政年份:
    1997
  • 资助金额:
    $ 39.85万
  • 项目类别:

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