权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
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
项目类别：
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

项目摘要

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经证明了可卡因依赖受试者纹状体水平上兴奋剂诱导的多巴胺释放的钝化。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纹状体，因为所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层（PFC）的病理激活和认知缺陷之间的关系，了解多巴胺在这一特定区域的调节作用是非常有趣的。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[11 C]FLB 457来测量PFC中苯丙胺诱导的多巴胺释放。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验证的成像范例来表征PFC中苯丙胺诱导的多巴胺释放，并将其与认知缺陷和复发联系起来。我们假设，安非他明诱导的多巴胺释放将减少中皮质多巴胺能系统的可卡因滥用者相对于健康的比较对象，并与认知功能障碍和复发时间较短。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负强化和成瘾复发的基础。孤啡肽（N/OFQ）是一种这样的肽类神经递质，其在啮齿动物成瘾模型中发挥抗应激作用并防止复发。以前的人类研究没有N/OFQ成瘾的特征。在目标2中，我们建议使用[11 C]NOP-1A PET来测量可卡因滥用者的伤害性阿片肽（NOP）受体的体内状态，并评估其与压力，焦虑，渴望和复发的关系。这一目标标志着在这一更新应用的新方向上迈出了谨慎的第一步，我们打算在可卡因依赖性方面进行进一步的实验，因为新的放射性示踪剂可用于对大脑应激的其他成分进行成像（例如，促肾上腺皮质激素释放激素、食欲素、加压素等，）抗应激系统（神经肽Y）。