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: 9722779
• 负责人: RAJESH NARENDRAN
• 金额: $ 13.06万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9722779
• 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; Drug Screening; 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; 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; radiotracer; receptor; relapse prediction; response; transmission process

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).

三个不同的成像小组在兴奋剂诱导的多巴胺释放中显示出钝化 可卡因依赖者的纹状体水平。这些研究的一个重要局限性是 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，因为所使用的配体不能提供足够的信噪比来量化D2/3受体 纹状体外区域。鉴于可卡因依赖的功能成像研究表明 在前额叶皮质(PFC)的病理性激活和认知障碍之间，人们对 了解多巴胺在这一特定区域的调节作用。在本奖项的前一个周期中，我们 验证了使用高亲和力多巴胺D2/3放射性示踪剂[11C]FLB457来测量苯丙胺诱导的 前额叶中的多巴胺释放。在目标1中，我们建议将这一新近验证的成像范例用于临床 可卡因依赖研究苯丙胺诱导的前额叶多巴胺释放及其相互关系 认知缺陷和旧病复发。我们假设苯丙胺诱导的多巴胺释放将是 与健康对照相比，可卡因滥用者中皮质多巴胺能系统降低 并与认知障碍和较少的复发时间有关。 最近的基础研究假设，调节压力的神经递质之间的失衡 而抗压力是负面强化和成瘾复发的基础。伤害素(Niciceptin，N/OFQ)就是这样一种 在成瘾的啮齿动物模型中发挥抗应激作用和防止复发的多肽神经递质。不是 以前的人类研究已经确定了N/OFQ成瘾的特征。在目标2中，我们建议使用[11C]NOP-1A PET检测可卡因滥用者体内伤害性阿片肽受体的状态，以及 评估它与压力、焦虑、渴望和复发的关系。这一目标标志着在新的 更新申请的方向，我们打算在可卡因方面进行进一步的实验 随着新型放射性示踪剂变得可用于成像脑应激的其他成分(例如， 促肾上腺皮质激素释放激素、增食欲素、加压素等)和抗应激系统(神经肽Y)。