PET Imaging of Cortical Dopamine Transmission in Cocaine Addiction

描述（由申请人提供）：在过去几年中，几个小组证明PET和SPECT神经受体成像技术不仅可以用于测量受体参数，还可以用于检测受体附近内源性递质浓度的急性波动（回顾，见Laruelle， 2000）。利用这种方法，我们和其他人报道了安非他明对若干神经精神疾病如精神分裂症（Breier et al., 1997; Laruelle et al., 1996）、注意缺陷多动障碍（Volkow et al., 2007）和成瘾（Malison et al., 1999; Martinez et al., 2007; Volkow et al., 1997）中DA传递的异常调节。这些研究的一个重要局限性是，D2受体和安非他明诱导的DA释放的测量主要局限于纹状体，因为所使用的配体没有提供足够的信噪比来量化纹状体外区域的D2受体。鉴于fMRI/代谢成像数据表明，在精神分裂症、多动症和成瘾等几种神经精神疾病中，执行功能的损伤与前额叶皮层的病理激活之间存在相关性，了解DA在这一特定区域的调节作用是非常有趣的（Bush et al., 2008; Callicott et al., 1999; Volkow and Fowler, 2000）。我们最近证明，高亲和力D2受体PET示踪剂[11C]FLB 457可用于测量安非他明诱导的多巴胺释放在感兴趣的皮质区域，包括背外侧前额叶皮层、内侧前额叶皮层、前扣带皮层、内侧颞叶（包括杏仁核和海马）和顶叶皮层。在本应用中，我们建议进一步验证使用[11C]FLB 457检测非人类灵长类动物（特异性目的1）和健康对照（特异性目的2-4）皮质区域内源性DA的变化。本申请中提出的验证[11C]FLB 457用于研究安非他明诱导的DA释放，将为研究界提供一种研究健康和疾病中皮质多巴胺传递的新工具。

DESCRIPTION (provided by applicant): Over the last few years, several groups demonstrated that PET and SPECT neuroreceptor imaging techniques can be used, not only to measure receptor parameters, but also to detect acute fluctuations in the concentration of endogenous transmitters in the vicinity of the receptors (for review, see Laruelle, 2000). Using this approach, we and others have reported an abnormal regulation of DA transmission following amphetamine in several neuropsychiatric disorders such as schizophrenia (Breier et al., 1997; Laruelle et al., 1996), attention-deficit hyperactivity disorder (Volkow et al., 2007) and addiction (Malison et al., 1999; Martinez et al., 2007; Volkow et al., 1997). An important limitation of these studies is the fact that measurements of D2 receptors and amphetamine-induced DA release were restricted mostly to the striatum because the ligands used did not provide enough signal to noise ratio to quantify D2 receptors in extrastriatal regions. Given that fMRI/metabolic imaging data suggests a correlation between impairments in executive function and pathological activation of the prefrontal cortex in several neuropsychiatric disroders such as schizophrenia, ADHD and addiction, it is of extreme interest to understand the regulatory role of DA in this particular region (Bush et al., 2008; Callicott et al., 1999; Volkow and Fowler, 2000). We recently demonstrated that the high affinity D2 receptor PET radiotracer [11C]FLB 457 can be used to measure amphetamine-induced DA release in the cortical regions of interest that include the dorsolateral prefrontal cortex, medial prefrontal cortex, anterior cingulate cortex, medial temporal lobe (which includes the amygdala and hippocampus) and parietal cortex. In this application, we propose to further validate the use of [11C]FLB 457 to detect changes in endogenous DA in the cortical regions in non human primates (specific aim 1) and healthy controls (specific aim 2-4). The proposed validation of [11C]FLB 457 to study amphetamine-induced DA release as outlined in this application will provide the research community with a new tool to study cortical dopamine transmission in both health and disease. PUBLIC HEALTH RELEVANCE: In this application we propose to further validate the use of [11C]FLB 457 to measure amphetamine- induced dopamine (DA) transmission in the human cortex.