Temporal Response of Dopamine to Alcohol Imaged via PET

描述（由申请人提供）：多巴胺是释放在纹状体响应酒精和其他药物，是至关重要的药物奖励，导致成瘾。我们对乙醇和其他滥用药物的神经反应的了解大部分是基于在药物滥用的小动物模型中使用微透析。由于微透析的时间分辨率差，不能捕获快速发生的神经化学事件。需要一种用于测定体内神经递质动态变化的方法，并且该提议的重点是开发这种方法。与微透析相比，PET具有许多优点，因为它是非侵入性的，定量的，并且可以以高的时间分辨率对大脑进行成像。迄今为止所缺乏的是动力学建模、实验设计和参数估计技术的必要结合，这些技术需要从神经递质浓度的短暂变化中推导出时间过程。 动态PET数据。 这项建议的具体目标是： 1.通过模拟真实数据和非线性参数估计，确定在存在非稳态内源性竞争物的情况下PET示踪剂与受体结合的两个动力学模型（一个使用动脉输入，另一个使用参考区域）的模型参数的可识别性。 2.评估通过应用先验知识提高模型参数可识别性的方法。 3.通过最优试验设计，最大化参数估计的精度。 4.使用本文开发的方法，结合小动物PET扫描仪，以充分表征急性酒精或可卡因激发后大鼠纹状体中的连续多巴胺动力学。 该提案的目标是创建必要的数学框架，以便小动物PET 用受体示踪剂的研究可用于精确地重建药物浓度的瞬时变化。 在选择性饲养的主动寻找酒精的大鼠和无酒精大鼠的大脑中内源性多巴胺。 我们的长期目标是探测神经递质的时间变化（例如，多巴胺和5-羟色胺），以确定神经递质对药物和其他刺激的反应的相关时间特征。我们试图确定神经递质反应动力学的长期变化是否是成瘾、记忆丧失或其他神经精神疾病的基础。待开发的方法将很容易转化为人类成像研究。

DESCRIPTION (provided by applicant): Dopamine is released in the striatum in response to alcohol and other drugs and is critical for drug reward that leads to addiction. Much of what we know about neural responses to ethanol and other drugs of abuse is based on the use of microdialysis in small animal models of drug abuse. Because of the poor temporal resolution of microdialysis, rapidly occurring neurochemical events cannot be captured. A method for assaying dynamic changes in neurotransmitters, in vivo, is needed and the focus of this proposal is the development of such methods. PET would offer many advantages over microdialysis because it is noninvasive, quantitative, and can image the brain with high temporal resolution. What has been lacking so far has been the necessary combination of kinetic modeling, experimental design and parameter estimation techniques required to derive a time course of the short-lived changes in neurotransmitter concentration from dynamic PET data. The specific aims for this proposal are: 1. To determine the identifiability -via simulations of realistic data and non-linear parameter estimation- of model parameters of a two kinetic models (one using arterial input, the other using a reference region) of a PET tracer binding to a receptor in the presence of a non-steady endogenous competitor. 2. To evaluate methods to improve the identifiability of model parameters by application of prior knowledge. 3. To maximize the precision of the parameter estimates via optimal experiment design. 4. To use the method developed herein, in conjunction with a small animal PET scanner, to fully characterize the continuous dopamine kinetics in the striata of rats following either acute alcohol or cocaine challenge. The goal of this proposal is to create the necessary mathematical framework so that small animal PET studies with receptor-tracers can be used to reconstruct precisely transient changes in concentration of endogenous dopamine in the brains of selectively bred rats who actively seek alcohol and of unselected rats. Our long-range goal is to probe temporal changes in neurotransmitters (e.g., dopamine and serotonin) in the brains of experimental animals, in vivo, to determine the relevant temporal characteristics of neurotransmitter responses to drugs and other stimuli. We seek to determine whether long-term changes in the dynamics of neurotransmitter responses underlie the development of addiction, loss of memory, or other neuropsychiatric conditions or diseases. The methods to be developed will easily translate to human imaging studies.