Temporal Response of Dopamine to Alcohol Imaged via PET

描述(申请人提供)：多巴胺在纹状体内释放，对酒精和其他药物的反应，是导致成瘾的药物奖励的关键。我们对乙醇和其他滥用药物的神经反应所知的很大一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较低，无法捕获快速发生的神经化学事件。需要一种在活体内分析神经递质动态变化的方法，本提案的重点是开发这种方法。与微透析相比，PET有许多优点，因为它是非侵入性的，定量的，并且可以以高时间分辨率成像大脑。到目前为止，所缺乏的是动力学建模、实验设计和参数估计技术的必要组合，以推导出神经递质浓度的短暂变化的时间进程 动态PET数据。 这项建议的具体目标是： 1.通过对真实数据的模拟和非线性参数估计，确定在非稳定的内源性竞争对手存在的情况下，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)的模型参数的可识别性。 2.应用先验知识对提高模型参数可辨识性的方法进行评价。 3.通过优化试验设计，使参数估计的精度达到最大。 4.使用本文开发的方法，结合小型动物PET扫描仪，全面表征急性酒精或可卡因攻击后大鼠纹状体中连续的多巴胺动力学。 这项提议的目标是建立必要的数学框架，以便小动物宠物 对受体示踪剂的研究可以用来精确地重建血药浓度的瞬时变化。 选择性繁殖的主动寻求酒精的大鼠和未选择的大鼠的大脑中的内源性多巴胺。 我们的长期目标是在活体内探测实验动物大脑中神经递质(如多巴胺和5-羟色胺)的时间变化，以确定神经递质对药物和其他刺激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、记忆力丧失或其他神经精神疾病或疾病发展的基础。将要开发的方法将很容易转化为人体成像研究。

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.