PET Imaging of Cortical Dopamine Transmission in Cocaine Addiction

可卡因成瘾过程中皮质多巴胺传输的 PET 成像

• 批准号: 9193064
• 负责人: RAJESH NARENDRAN
• 金额: $ 56.17万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9193064
• 关键词: Abstinence; Addictive Behavior; Affinity; Age; Agonist; Amphetamines; Amygdaloid structure; Anxiety; Attention; Award; Binding; Brain; Chronic; Chronic Disease; Clinical Research; Cocaine; Cocaine Dependence; Cognition; Cognitive deficits; Conflict (Psychology); Corpus striatum structure; Corticotropin-Releasing Hormone; Decision Making; Detection; Development; Dopamine; Dynorphins; Female; Functional Imaging; Funding; Gender; Human; Image; Impaired cognition; Intoxication; Investigation; Knowledge; Lead; Ligands; Measurement; Measures; Mediating; Memory; Midbrain structure; Motor; Negative Reinforcements; Neurocognitive Deficit; Neuropeptides; Neurotransmitters; Nociception; Noise; Opioid Peptide; Oral; Outcome Measure; Pathologic; Peptide Receptor; Peptides; Pharmaceutical Preparations; Phase; Positive Reinforcements; Positron-Emission Tomography; Preclinical Drug Evaluation; Prefrontal Cortex; Raclopride; Relapse; Risk; Rodent; Rodent Model; Role; Sampling; Scanning; Short-Term Memory; Signal Transduction; Smoking Status; Standardization; Stress; System; Time; Up-Regulation; Urine; Validation; Vasopressins; Ventral Striatum; Withdrawal; addiction; cocaine exposure; cognitive function; contingency management; craving; endogenous opioids; experimental study; follow-up; hypocretin; imaging study; in vivo; interest; neurochemistry; neuropeptide Y; nociceptin; novel; preference; prevent; processing speed; public health relevance; radiotracer; receptor; relapse prediction; response; transmission process

 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).

 描述（由申请人提供）：三个不同的成像组已证明可卡因依赖受试者纹状体水平的兴奋剂诱导的多巴胺释放减弱。这些研究的一个重要局限性是，D2/3 受体和安非他明诱导的多巴胺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 D2/3 受体。鉴于可卡因依赖的功能成像研究表明前额皮质 (PFC) 的病理激活与认知缺陷之间存在关系，因此了解多巴胺在这一特定区域的调节作用非常有意义。在该奖项的上一个周期中，我们验证了使用高亲和力多巴胺 D2/3 放射性示踪剂 [11C]FLB 457 来测量 PFC 中安非他明诱导的多巴胺释放。在目标 1 中，我们建议在可卡因依赖的临床研究中使用这种最近经过验证的成像范例来表征前额皮质中安非他明诱导的多巴胺释放，并将其与认知缺陷和复发联系起来。我们假设，相对于健康对照受试者，可卡因滥用者的中皮质多巴胺能系统中苯丙胺诱导的多巴胺释放会减少，并且与认知障碍和复发时间缩短有关。 最近的基础研究假设，调节压力和抗压力的神经递质之间的不平衡是成瘾的负强化和复发的基础。伤害感受肽 (N/OFQ) 就是这样一种肽类神经递质，在啮齿动物成瘾模型中发挥抗应激作用并防止复发。此前还没有人类研究表明 N/OFQ 与成瘾有关。在目标 2 中，我们建议使用 [11C]NOP-1A PET 测量可卡因滥用者体内伤害性阿片肽 (NOP) 受体的状态，并评估其与压力、焦虑、渴望和复发的关系。这一目标标志着这一更新应用朝着新方向迈出了谨慎的第一步，随着新型放射性示踪剂可用于对大脑压力的其他成分（例如促肾上腺皮质激素释放激素、食欲素、加压素等）和抗压力系统（神经肽 Y）进行成像，我们打算在可卡因依赖方面进行进一步的实验。