Individual Differences in Extrastriatal DA Release

描述(由申请人提供)：个性和遗传因素都与精神刺激性药物滥用的易感性有可靠的联系。这种脆弱性中的一部分可能表现为对心理刺激剂的认知和主观反应的个体差异。纹状体多巴胺(DA)结合的PET和SPECT成像研究表明，精神刺激剂释放的DA量存在显著的个体差异。DA释放的这些差异与这些药物的主观影响有关。研究还表明，基线变量，如纹状体的基础D2/D3结合，以及寻求新奇/感觉的个性特征，可能预测对心理刺激的反应。不幸的是，这篇文献一直局限于纹状体DA功能的测量，因为用大多数可用的DA受体配体成像纹状体外DA是困难的。然而，大量证据表明，纹状体外区域也参与了与药物滥用有关的过程。我们建议使用[18F]FallyPride在54名健康受试者中检查纹状体外DA功能、个性和对口服苯丙胺(d-amph)的反应性之间的关系。[18F]FallyPride是一种高亲和力的D2/D3配体，标记纹状体和纹状体外受体，对内源性DA水平敏感，使其能够索引由精神刺激剂释放的内源性DA的量。在健康受试者中使用[18F]FallyPride PET的初步数据表明，d-amph在纹状体中产生显著的DA释放。纹状体和纹状体外区DA的释放量与D-AMPH的客观精神运动改善有关。然而，DA的释放和d-amph的主观效应之间的显著关联局限于纹状体外区域，特别是扣带回的部分。与动物模型一致的是，数据表明，高感觉寻求的个体在纹状体和中脑DA产生区域的基础D2/D3结合水平较低(可能反映了自身受体密度的降低)。本提案的目的是在大样本受试者中确认和扩大这些研究结果。此外，我们还旨在验证儿茶酚-O-甲基转移酶Val158met多态影响DA释放的假说。将通过专门招聘同等数量的MET/MET、VAL/MET和VAL/VAL受试者来评估这一点。此外，我们还将对其他几个与药物滥用风险相关的候选基因是否对基线D2/D3结合和/或DA释放产生可测量的影响进行初步探索。最后，为了更好地理解DA的区域性调节，我们将研究DA在中脑、纹状体、丘脑和皮质中的功能之间的相互关系。总而言之，这项研究将提供独特的信息，说明人类DA系统组织中的个体差异如何与个性、遗传学以及心理刺激剂的主观和认知影响有关。

DESCRIPTION (provided by applicant): Both personality and genetic factors are reliably associated with vulnerability for developing psychostimulant drug abuse. Some of this vulnerability is likely expressed as individual differences in the cognitive and subjective response to psychostimulants. PET and SPECT imaging studies of striatal dopamine (DA) binding indicate the presence of significant individual differences in the amount of DA released by psychostimulants. these differences in DA release are associated with the subjective effects of these agents. Studies also suggest that baseline variables, such as basal D2/D3 binding in the striatum, and novelty/sensation seeking personality traits may predict responsiveness to psychostimulants. Unfortunately, this literature has been limited to measurement of striatal DA functioning due to difficulties imaging extrastriatal DA with most available DA receptor ligands. However, substantial evidence indicates that extrastriatal regions are also involved in processes related to drug abuse. We propose to examine the relationship between extrastriatal DA functions, personality and responsiveness to oral amphetamine (d- AMPH) using [18F]Fallypride in 54 healthy human subjects. [18F]Fallypride is a high affinity D2/D3 ligand that labels both striatal and extrastriatal receptors and is sensitive to endogenous DA levels allowing it to index the amount of endogenous DA released by psychostimulants. Preliminary data using [18F]Fallypride PET in healthy subjects indicate that d-AMPH produces significant DA release in the striatum. The amount of DA released in both the striatum and extrastriatal regions was associated with objective psychomotor improvements on d-AMPH. However, significant associations between DA release and subjective effects of d-AMPH localized to extrastriatal regions, especially portions of the cingulate. Consistent with animal models, the data indicate that individuals high on sensation seeking have lower basal D2/D3 binding levels in both the striatum and midbrain DA producing regions (likely reflecting reduced autoreceptor density). The present proposal aims to confirm and extend these findings in a large sample of subjects. We additionally aim to test hypothesis that the catechol-o-methyltransferase val158met polymorphism effects DA release. This will be assessed by specifically recruiting equal numbers of met/met, val/met and val/val subjects. We will additionally provide an initial exploration of whether several additional candidate genes that are related to risk for drug abuse have a measurable effect on either baseline D2/D3 binding and/or DA release. Finally, in order to better understand the regional regulation of DA, we will examine the inter-relations between DA functioning in the midbrain, striatum, thalamus and cortex. Taken together, the study will provide unique information on how individual differences in the organization of the human DA system are associated with personality, genetics and the subjective and cognitive effects of psychostimulants.