Dynamics of in vivo dopamine release

描述（由申请人提供）：为了应对不断变化的世界，生物体需要适应性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”通路的神经元回路被激活。 这个回路中的信息处理引导有机体对奖励获取做出最佳反应。 多巴胺长期以来一直被认为是这一通路中的一种重要神经递质，这一概念得到了我们自己的研究结果的有力支持，这些研究结果使用了在现有赠款支持下开发的工具。 同样，生物体也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。 尽管厌恶性通路的特征还不太清楚，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研究的支持。 多巴胺和去甲肾上腺素参与这些关键回路是它们的不平衡与各种疾病有关的核心原因，这些疾病包括精神障碍，如精神分裂症和抑郁症，以及行为障碍，如药物滥用和肥胖症。 拟议研究的目标是开发工具，以亚秒级的时间尺度和亚毫米级的时间分辨率来评估脑内的儿茶酚胺神经传递。 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释放的儿茶酚胺。 我们将开发和修改辅助技术，以揭示这些物质释放后受体介导的作用。 这项建议的目的如下。 1. 描述离子电渗疗法的空间和时间特性。 在上一个项目期间，我们的特点离子电渗，并透露，它有一个主要的贡献，从电渗。 我们的方法能够将已知量的试剂递送到细胞外空间中。 需要一个基于质量传输理论的射血率及其空间分布，以了解其对附近受体的影响。 2. 表征神经递质释放产生的空间分布的化学和电信息 以及在脑内释放所引起的电活动的变化。 我们已经开发出仪器，使神经元的电活动，以同时测量神经递质释放的测量。 在这里，我们建议评估这个电化学电生理系统耦合到离子电渗，使用一个很好的特点，脑切片制备。 3. 描述多巴胺神经传递对延髓核中靶神经元对奖赏刺激的反应的影响。 使用新的离子电渗和电生理方法，结合我们的电化学技术检测多巴胺，我们将探索多巴胺影响不同类型的靶神经元的方式。 4. 描述去甲肾上腺素神经传递对奖赏和厌恶刺激的反应。 我们的离子电渗，电生理和电化学方法将被用来了解这种释放活动的刺激处理。

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.