Individual Differences in Extrastriatal DA Release

描述（由申请人提供）：人格和遗传因素都与发展精神兴奋剂药物滥用的脆弱性可靠相关。这种脆弱性可能表现为对精神兴奋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，精神兴奋剂释放的DA量存在显着的个体差异。DA释放的这些差异与这些药物的主观效应有关。研究还表明，基线变量，如纹状体中的基础D2/D3结合，以及寻求新奇/感觉的人格特质可以预测对精神兴奋剂的反应。不幸的是，由于使用大多数可用的DA受体配体难以对纹外DA进行成像，因此该文献仅限于测量纹状DA功能。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。我们建议在54名健康受试者中使用[18 F]Fallypride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。[18 F]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，使其能够指示精神兴奋剂释放的内源性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释放的DA量与d-AMPH的客观精神状态改善相关。然而，DA的释放和d-AMPH的主观影响之间的显着关联定位到纹状体外区域，特别是扣带回的部分。与动物模型一致，数据表明，感觉寻求高的个体在纹状体和中脑DA产生区的基础D2/D3结合水平较低（可能反映了自身受体密度降低）。目前的建议旨在确认和扩大这些调查结果在一个大样本的主题。我们还旨在检验儿茶酚-o-甲基转移酶val 158 met多态性影响DA释放的假设。这将通过专门招募相同数量的met/met、瓦尔/met和瓦尔/瓦尔受试者进行评估。我们还将提供一个初步的探索，是否有几个额外的候选基因，与药物滥用的风险有一个可测量的影响，无论是基线D2/D3结合和/或DA释放。最后，为了更好地了解DA的区域调节，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。总之，这项研究将提供关于人类DA系统组织中的个体差异如何与个性，遗传学以及精神兴奋剂的主观和认知效应相关的独特信息。

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.