Individual Differences in Extrastriatal DA Release

人格和遗传因素都与易患精神兴奋剂有关 吸毒这种脆弱性的一部分可能表现为认知和心理方面的个体差异， 对精神兴奋剂的主观反应纹状体多巴胺（DA）的PET和SPECT成像研究 结合表明存在显着的个体差异的量释放的DA 精神兴奋剂DA释放的这些差异与这些因素的主观影响有关。 剂.研究还表明，基线变量，如纹状体中的基础D2/D3结合， 寻求新奇/感觉的人格特质可以预测对精神兴奋剂的反应性。不幸的是， 由于成像困难，该文献仅限于测量纹状体DA功能 纹状体外DA与大多数可用的DA受体配体。然而，大量证据表明， 纹状体外区域也参与与药物滥用有关的过程。我们建议研究 纹状体外DA功能、个性和对口服安非他明（d- AMPH）使用[18F]Fallypride在54名健康人类受试者中进行。[18F]Fallypride是一种高亲和力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， 精神兴奋剂释放的内源性多巴胺的量使用[18F]Fallypride PET的初步数据 健康受试者表明d-AMPH在纹状体中产生显著的DA释放。DA的数量 在纹状体和纹状体外区域的释放与客观精神障碍有关 对d-AMPH的改进。然而，DA释放和主观影响之间的显着关联， d-AMPH定位于纹状体外区，特别是扣带回的部分。与动物一致 模型，数据表明，高感觉寻求的个体具有较低的基础D2/D3结合水平， 纹状体和中脑DA产生区（可能反映了自身受体密度的降低）。的 本提案旨在在大样本受试者中证实和扩展这些发现。我们另外 目的验证儿茶酚氧位甲基转移酶val 158 met基因多态性影响多巴胺释放的假说。 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 将另外提供一个初步的探索，是否有几个额外的候选基因，与 药物滥用风险对基线D2/D3结合和/或DA释放有可测量的影响。最后， 为了更好地理解区域性的发展援助管制，我们将研究发展援助与区域性发展援助之间的相互关系， 在中脑、纹状体、丘脑和皮质中发挥作用。总的来说，这项研究将提供独特的 关于人类DA系统组织中的个体差异如何与 人格、遗传以及精神兴奋剂的主观和认知影响。

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.