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

基本信息

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
项目类别：
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

项目摘要

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).

三个不同的成像组已证明兴奋剂诱导的多巴胺释放在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 受体和安非他明诱导的多巴胺释放的测量主要限于因为所使用的配体没有提供足够的信噪比来量化纹状体中的 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，前额皮质（PFC）的病理性激活和认知缺陷之间的关系非常令人感兴趣了解多巴胺在这个特定区域的调节作用。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 来测量安非他明诱导的 PFC 中的多巴胺释放。在目标 1 中，我们建议在临床中使用这种最近经过验证的成像范例可卡因依赖性研究，以表征苯丙胺诱导的 PFC 中多巴胺释放，并将其关联起来认知缺陷和复发。我们假设安非他明诱导的多巴胺释放将与健康相比，可卡因滥用者的中皮质多巴胺能系统下降受试者并与认知障碍和复发时间较短有关。最近的基础研究假设调节压力的神经递质之间存在不平衡抗压力是成瘾的负强化和复发的基础。痛敏肽 (N/OFQ) 就是其中之一肽神经递质，在啮齿动物成瘾模型中发挥抗应激作用并防止复发。不之前的人类研究已经描述了成瘾中的 N/OFQ。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，以及评估它与压力、焦虑、渴望和旧病复发的关系。这一目标标志着新的目标迈出了谨慎的第一步此更新申请的方向，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可用于对大脑压力的其他组成部分进行成像（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）。