PET Imaging of Cortical Dopamine Transmission in Cocaine Addiction

 描述(申请人提供)：三个不同的成像小组已经证明，在可卡因依赖的受试者中，刺激剂诱导的纹状体水平的多巴胺释放被钝化。这些研究的一个重要局限性是，对D2/3受体和苯丙胺诱导的多巴胺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D2/3受体。鉴于可卡因依赖的功能成像研究表明前额叶皮质(PFC)的病理性激活与认知障碍之间的关系，了解多巴胺在这一特定区域的调节作用是非常有意义的。在本奖项的前一个周期中，我们验证了高亲和力多巴胺D2/3放射性示踪剂[11C]FLB457的使用，以测量苯丙胺在PFC中诱导的多巴胺释放。在目标1中，我们建议在可卡因依赖的临床研究中使用这一最近得到验证的成像范式来表征苯丙胺诱导的前额叶多巴胺释放，并将其与认知缺陷和复发联系起来。我们假设，与健康对照受试者相比，安非他明诱导的多巴胺释放在可卡因滥用者的中脑皮层多巴胺能系统中将减少，并与认知障碍和较短的复发时间有关。最近的基础研究假设，调节应激和抗应激的神经递质之间的失衡是成瘾的负面强化和复发的基础。Niciceptin(N/OFQ)是一种在成瘾啮齿动物模型中发挥抗应激作用和防止复发的多肽类神经递质。此前没有一项人类研究将N/OFQ描述为成瘾。在目标2中，我们建议使用[11C]NOP-1APET来检测可卡因滥用者体内伤害性阿片肽(NOP)受体的状态，并评估其与应激、焦虑、渴求和复发的关系。这一目标标志着这一更新应用的新方向迈出了谨慎的第一步，我们打算随着新的放射性示踪剂的出现而对可卡因依赖进行进一步的实验，以成像大脑应激的其他成分(例如，促肾上腺皮质激素释放激素、食欲素、加压素等)和抗应激系统(神经肽Y)。

 DESCRIPTION (provided by applicant): Three different imaging groups have demonstrated a blunting in stimulant induced dopamine release at the level of the striatum in cocaine dependent subjects. An important limitation of these studies is the fact that measurements of D2/3 receptors and amphetamine-induced dopamine release were restricted mostly to the striatum because the ligands used did not provide enough signal to noise ratio to quantify D2/3 receptors in extrastriatal regions. Given that functional imaging studies in cocaine dependence suggests a relationship between pathological activation of the prefrontal cortex (PFC) and cognitive deficits it is of extreme interest to understand the regulatory role of dopamine in this particular region. During the previous cycle of this award we validated the use of the high affinity dopamine D2/3 radiotracer [11C]FLB 457 to measure amphetamine-induced dopamine release in the PFC. In aim 1 we propose to use this recently validated imaging paradigm in a clinical study in cocaine dependence to characterize amphetamine-induced dopamine release in the PFC, and relate it to cognitive deficits and relapse. We hypothesize that amphetamine-induced dopamine release will be decreased in the mesocortical dopaminergic system in cocaine abusers relative to healthy comparison subjects and be associated with cognitive impairments and less time to relapse. Recent basic investigations postulate that an imbalance between neurotransmitters that regulate stress and anti-stress underlie negative reinforcement and relapse in addiction. Nociceptin (N/OFQ) is one such peptide neurotransmitter that exerts anti-stress effects and prevents relapse in rodent models of addiction. No previous human studies have characterized N/OFQ in addiction. In aim 2, we propose to use [11C]NOP-1A PET to measure the in vivo status of nociceptive opioid peptide (NOP) receptors in cocaine abusers, and evaluate its relationship with stress, anxiety, craving, and relapse. This aim marks a cautious first step in a new direction for this renewal application, which we intend to follow up with further experiments in cocaine dependence as novel radiotracers become available to image other components of the brain stress (e.g., corticotrophin releasing hormone, orexin, vasopressin, etc.,) and anti-stress system (neuropeptide Y).