PET Imaging of Cortical Dopamine Transmission in Cocaine Addiction

描述（由申请人提供）：在过去几年中，几个研究组证明PET和SPECT神经受体成像技术不仅可用于测量受体参数，还可用于检测受体附近内源性递质浓度的急性波动（综述见Laruelle，2000）。使用这种方法，我们和其他人已经报道了在几种神经精神疾病如精神分裂症中安非他明后DA传递的异常调节（Breier等人，1997; Laruelle等人，1996）、注意力缺陷多动障碍（Attention-Deficit Hyperactivity Disorder，2007）和成瘾（Malison等人，1999; Martinez等人，2007年; Wavelow等人，1997年）。这些研究的一个重要限制是，D2受体和安非他明诱导的DA释放的测量主要限于纹状体，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几种神经精神障碍如精神分裂症、ADHD和成瘾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，因此理解DA在该特定区域中的调节作用是极其有趣的（Bush et al.，2008; Callicott等人，1999年; Escherow和Fowler，2000年）。我们最近证明，高亲和力D2受体PET放射性示踪剂[11 C]FLB 457可用于测量感兴趣的皮质区域中安非他明诱导的DA释放，这些皮质区域包括背外侧前额叶皮质、内侧前额叶皮质、前扣带皮质、内侧颞叶（包括杏仁核和海马）和顶叶皮质。在本申请中，我们建议进一步验证使用[11 C]FLB 457检测非人灵长类动物（具体目标1）和健康对照（具体目标2-4）皮质区域中内源性DA的变化。如本申请中所述，[11 C]FLB 457用于研究苯丙胺诱导的DA释放的拟议验证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。 公共卫生相关性： 在本申请中，我们提出进一步验证使用[11 C]FLB 457来测量苯丙胺诱导的多巴胺（DA）在人类皮层中的传递。

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.