Imaging Synaptic Density in the Cocaine-Addicted Brain In Vivo using 11C UCB J PET

使用 11C UCB J PET 对可卡因成瘾大脑中的突触密度进行体内成像

基本信息

批准号：
9335542
负责人：
ROBERT T MALISON
金额：
$ 20.94万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335542
关键词：
Abstinence Animals Basic Science Behavior Brain Brain imaging Brain region Chronic Clinical Cocaine Cocaine Dependence Corpus striatum structure Decision Making Dendritic Spines Development Disease Drug usage Epilepsy Exploratory/Developmental Grant for Diagnostic Cancer Imaging Exposure to Functional disorder Funding Future Glycoproteins Goals Gold Human Image Imaging Device Impairment In Vitro Inpatients Intoxication Measures Medial Medicine Methodology Modeling Modernization Molecular Monitor Neurobiology Neurons Nucleus Accumbens Outcome Patients Pattern Pharmaceutical Preparations Population Positron-Emission Tomography Prefrontal Cortex Primates Pyramidal Cells Refractory Regimen Relapse Research Rewards Rodent Seminal Stratum Spinosum Structure Synapses Synaptic plasticity Synaptophysin Testing Time Toxicology Tracer Urine Validation Variant Ventral Striatum Withdrawal addiction behavioral sensitization craving density drug abstinence drug craving drug of abuse human imaging imaging properties imaging study in vivo insight neuroadaptation novel optimism pre-clinical preclinical study radiotracer receptor tool uptake working group

项目摘要

Project Summary A major goal of modern addiction research is to understand the neural adaptations that underlie the chronic, maladaptive and, for many, treatment-‐refractory behaviors produced by drugs of abuse, including cocaine. Considerable optimism exists in this regard, as powerful preclinical tools and well-‐established animal models have resulted in dramatic advances in our understanding of the molecular and cellular mechanisms of cocaine-‐ related plasticity [1]. Nonetheless, a considerable gap remains in the clinical-‐translational testing and validation of such preclinical findings in human cocaine addiction. In seminal preclinical studies nearly 20 years ago, Robinson & Kolb [2, 3] demonstrated enduring increases in synaptic (i.e., dendritic spine) density in both the nucleus accumbens [NAc] and medial prefrontal cortex [mPFC]) of rodents following behaviorally sensitizing regimens of cocaine. Their findings were compelling and suggested an important pathophysiological mechanism – aberrant structural synaptic plasticity – whereby cocaine might produce the chronic, recalcitrant behaviors (e.g., craving, compulsive use, and relapse) so seemingly ‘hard-‐ wired’ in those suffering from the disorder. Our group has developed a novel radiotracer, 11C-‐UCB-‐J, for imaging synaptic density in the living human brain using positron-‐emission tomography (PET) [62, 63]. Thus, the current Cutting Edge Basic Research Award (CEBRA)/R21 application seeks to apply this breakthrough methodology to explore whether observations of increased synaptic density in the NAc and mPFC of rodents are recapitulated in cocaine dependent (CD) humans. If achieved, the current study would have a major impact, providing powerful clinical-‐translational support for aberrant brain structure at the synaptic level, setting the stage for future studies of the relationship of such aberrant synaptic density to withdrawal/abstinence, cocaine-‐related behavior and clinical outcome.

项目概要现代成瘾研究的一个主要目标是了解慢性成瘾背后的神经适应，滥用药物（包括可卡因）产生的适应不良和对许多人来说难以治疗的行为。在这方面存在相当大的优化，因为强大的临床前工具和完善的动物模型使我们对可卡因的分子和细胞机制的理解取得了巨大的进步—— 相关的可塑性[1]。尽管如此，临床转化测试和验证仍然存在相当大的差距。人类可卡因成瘾的临床前发现。在近 20 年前的开创性临床前研究中，Robinson 和 Kolb [2, 3] 证明了伏隔核 [NAc] 和内侧前额皮质 [mPFC] 中的突触（即树突棘）密度啮齿动物遵循可卡因的行为致敏方案。他们的发现令人信服且具有启发性。一个重要的病理生理机制——异常的结构突触可塑性——可卡因可能会通过这种机制产生慢性的、顽固的行为（例如，渴望、强迫性使用和复发），因此看起来“很难” 那些患有这种疾病的人“连线”。我们的小组开发了一种新型放射性示踪剂 11C-UCB-J，用于对活人大脑中的突触密度进行成像。使用正电子发射断层扫描 (PET) [62, 63]。因此，当前的尖端基础研究奖 (CEBRA)/R21 申请旨在应用这一突破性方法来探索观察结果是否啮齿类动物 NAc 和 mPFC 中突触密度的增加在可卡因依赖 (CD) 人类中得到了重现。如果实现，当前的研究将产生重大影响，为以下方面提供强大的临床转化支持：突触水平的异常大脑结构，为未来研究这种关系奠定了基础异常的突触密度导致戒断/戒断、可卡因相关行为和临床结果。