Cognitive effects of anesthetics and dopamine transport

麻醉药和多巴胺转运的认知影响

• 批准号: 6472109
• 负责人: John R Votaw
• 金额: $ 19.62万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6472109
• 关键词: Primates; anesthetics; clinical research; cognition disorders; dialysis; dopamine transporter; drug adverse effect; drug interactions; human subject; immunocytochemistry; intermolecular interaction; laboratory rat; neurotransmitter metabolism; positron emission tomography; protein kinase C

Description (provided by applicant): This grant is being submitted in response to the program announcement, PA-96-026, "Molecular Pharmacology of Anesthetic Action." The announcement states (in part) ." . .it has been difficult to assign a direct correlation between molecular events that are influenced by anesthetics and the physiological effects that subsequently occur." In the preliminary data section, we present evidence of molecular interaction between volatile anesthetics and the dopamine transporter (DAT). Our model is: Initially, there is normal trafficking between expressed and cytoplasmic (DAT). At induction of anesthesia, some anesthetic binds directly to the DAT and some activates protein kinase C (PKC) causing some internalization of DAT. The extracellular concentration of DA increases because fewer expressed DAT result in less reuptake of DA. Continued release of DA is inhibited by a feedback mechanism signaled from extracellular DA. During prolonged anesthesia, the extracellular DA is metabolized, which decreases its concentration while increasing the concentration of its metabolites. After cessation of anesthesia, the anesthetic first clears from the body allowing the expressed DAT to function and PKC to return to the inactive state. Then, DA concentration begins to recover. After the system has nearly recovered, the DAT and extracellular DA concentrations return to normal but additional DA must be synthesized to replenish that lost to metabolism. Cognitive ability normalizes after all subsystems return to baseline values. We propose to test this model with a series of in vitro, rat, non-human primate and human studies and to determine the physiological significance of these changes as they relate to cognitive performance in humans through 3 specific aims: Specific Aim 1: Analyze the DAT-anesthetic interaction at the cellular and sub-cellular level. We hypothesize that DAT-anesthetic interaction will be significant at clinically relevant concentrations for certain anesthetics and, we expect to see reduced [18F]FECNT binding and [3H]dopamine uptake following anesthetic administration due to trasnporter internalization. Specific Aim 2: Characterize the DAT-anesthetic interaction in intact living tissue. We expect to confirm DAT internalization and observe an initial increase in extracellular DA followed by decreased DA and increased metabolites indicating decreased functioning of the DAT. Results of these experiments in comparison with aim 1 will determine if interaction with other neural systems is important. They will also provide a direct calibration for interpreting the PET results in aim 3. Specific Aim 3: Measure the duration of decreased [18F]FECNT binding potential following anesthesia in humans and correlate with cognitive functioning. Using the results from aims 1 and 2, this PET experiment will give information about DAT expression in humans following anesthesia. We expect the time course to normalization of the binding potential and cognitive performance to correlate well.

描述（由申请人提供）：该赠款正在回应中提交 在计划公告中，PA-96-026，“麻醉分子药理学 行动。“公告指出（部分）。” 。很难 分配受影响的分子事件之间的直接相关性 麻醉药和随后发生的生理作用。” 初步数据部分，我们提供了分子相互作用的证据 挥发性麻醉和多巴胺转运蛋白（DAT）。我们的模型是： 最初，表达和细胞质（DAT）之间存在正常运输。 诱导麻醉时，一些麻醉剂直接与DAT结合，有些麻醉症 激活蛋白激酶C（PKC），导致DAT的某些内在化。这 DA的细胞外浓度增加，因为更少的表达结果 在较少的DA重新摄取中。持续释放DA被反馈抑制 来自细胞外DA的机制。在长期麻醉期间， 细胞外DA被代谢，从而降低其浓度 增加其代谢物的浓度。停止麻醉后， 麻醉剂首先从身体中清除，允许表达的dat到 功能和PKC返回到无效状态。然后，DA浓度开始 恢复。系统几乎恢复后，DAT和细胞外DA 浓度恢复正常，但必须将额外的DA合成为 补充了那些因代谢而失去的。认知能力毕竟正常 子系统返回基线值。我们建议用 一系列体外，大鼠，非人类灵长类动物和人类研究，并确定 这些变化与认知相关的生理意义 通过3个特定目的在人类中的表现：特定目标1：分析 细胞和亚细胞水平的Dat-Ansesthetic相互作用。我们 假设在临床上，Dat-Anesthethetic的相互作用将很重要 某些麻醉剂的相关浓度，我们希望看到减少 [18f]麻醉剂后的FECNT结合和[3H]多巴胺摄取 由于跨孢子虫的内在化。特定目标2：特征 完整活组织中的Dat-Ansesthetic相互作用。我们希望确认DAT 内在化并观察到细胞外DA的初始增加，然后观察 DA的减少和代谢增加，表明该功能降低 dat。与AIM 1相比，这些实验的结果将确定是否确定 与其他神经系统的互动很重要。他们还将提供 用于解释宠物的直接校准在目标3中。特定目标3： 测量降低[18F] FECNT结合势的持续时间 人类麻醉，与认知功能相关。使用 AIM 1和2的结果，该宠物实验将提供有关DAT的信息 麻醉后人类的表达。我们希望时间课程 结合潜力和认知性能的归一化以相关 出色地。