Dynamics of in vivo dopamine release

描述(申请人提供)：为了对不断变化的世界作出反应，生物体需要适应的过程才能适当地发挥作用。在目标导向的行为中，一组形成大脑“奖励”路径的神经元回路被激活。这个回路中的信息处理引导生物体对获得奖赏做出最佳反应。长期以来，多巴胺一直被认为是这一途径中的一种重要的神经递质，这一概念得到了我们自己的发现的有力支持，这些工具是在现有赠款的支持下开发的。类似地，生物体需要一套相反的回路，对令人厌恶的事件和预测它们的刺激做出反应。尽管厌恶通路的特征不是很好，但去甲肾上腺素神经传递的增加与这种行为有关，这一概念得到了我们自己的研究的支持。多巴胺和去甲肾上腺素参与了这种关键回路，这是它们失衡的核心原因，从精神分裂症和抑郁症等精神障碍到药物滥用和肥胖等行为障碍，它们的失衡与各种疾病有关。这项拟议研究的目标是开发工具，以亚秒时间尺度和亚毫米时间分辨率评估儿茶酚胺在大脑中的神经传递。我们将在碳纤维微电极上使用快速扫描循环伏安法来测量神经元儿茶酚胺的释放。我们将开发和修改辅助技术，以揭示这些物质释放后的受体介导的作用。这项建议有以下目标。1.研究了离子导入的时空特征。在前一个项目期间，我们对离子导入进行了表征，并揭示了它对电渗透的主要贡献。我们的方法能够将已知数量的试剂输送到细胞外空间。为了了解它对附近受体的影响，需要一个基于质量传输的射出速率及其空间分布的理论。2.描述神经递质释放所产生的空间分布的化学和电学信息 以及它在大脑中的释放所引起的电活动的变化。我们已经开发出一种仪器，可以在测量神经递质释放的同时测量神经元的电活动。在这里，我们建议使用具有良好特性的脑片制备来评估这种与离子导入相耦合的电化学-电生理系统。3.表征多巴胺神经传递对伏隔核靶神经元对奖赏刺激的影响。通过使用新的离子导入和电生理方法与我们的电化学技术相结合来检测多巴胺，我们将探索多巴胺如何影响不同类型的靶神经元。4.表征去甲肾上腺素对奖赏和厌恶刺激的神经传递。我们的离子电泳法、电生理学和电化学法将被用来理解刺激处理过程中的这种释放活动。

DESCRIPTION (provided by applicant): To respond to a constantly changing world, an organism needs adaptive processes to function appropriately. A group of neuronal circuits that form the brain "reward" pathway is activated during goal-directed behaviors. Information processing within this circuit guides the organism to respond optimally for reward acquisition. Dopamine has long been identified as an important neurotransmitter in this pathway, and this concept is given strong support by our own findings using tools that were developed with the support of the existing grant. Similarly, the organism requires an opposing set of circuitry responsive to aversive events and stimuli that predict them. Although the aversive pathways are less well characterized, increased norepinephrine neurotransmission has been implicated in such behaviors, a concept supported by our own research. The involvement of dopamine and norepinephrine in such critical circuits is the central reason that their imbalance has been implicated in a variety of conditions ranging from mental disorders such as schizophrenia and depression to behavioral disorders such as drug abuse and obesity. The goal of the proposed research is to develop tools to evaluate catecholamine neurotransmission within the brain on a subsecond time scale and with submillimeter time resolution. We will use fast-scan cyclic voltammetry at carbon-fiber microelectrodes for measurements of catecholamine release from neurons. We will develop and modify ancillary techniques to reveal the receptor-mediated actions of these substances following their release. This proposal has the following aims. 1. Characterize the spatial and temporal characteristics of iontophoresis. During the previous project period we characterized iontophoresis and revealed that it has a major contribution from electroosmosis. Our approach enables delivery of known amounts of reagents into the extracellular space. A mass-transport based theory of the ejection rate and its spatial distribution is required to understand its effects on nearby receptors. 2. Characterize the spatially distributed chemical and electrical information that arises from neurotransmitter release and the changes in electrical activity that are evoked by its release within the brain. We have developed instrumentation that enables the electrical activity of neurons to be measured simultaneously with measurements of neurotransmitter release. Here we propose to evaluate this electrochemical-electrophysiological system coupled to iontophoresis using a well characterized brain slice preparation. 3. Characterize the effects of dopamine neurotransmission on its target neurons in the nucleus accumbens in response to rewarding stimuli. With the use of the new iontophoresis and electrophysiological approaches that are coupled to our electrochemical techniques for detecting dopamine, we will explore the ways in which dopamine affects the different types of target neurons. 4. Characterize norepinephrine neurotransmission in response to rewarding and aversive stimuli. Our iontophoretic, electrophysiological, and electrochemical approaches will be used to understand this release activity on processing of stimuli.