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.

项目摘要现代成瘾研究的一个主要目标是了解慢性慢性的神经适应性适应不良的和许多治疗 - 包括可卡因在内的滥用药物产生的不法行为行为。作为强大的临床前工具和建立的动物模型，这种常规的临时工具存在很大的乐观我们对可卡因的分子和细胞机制的理解带来了巨大的进步 - 相关的可塑性[1]。尽管如此，临床上仍然存在相当大的差距 - 翻译测试和验证人类可卡因成瘾中的这种临床前发现。在大约20年前的开创性临床前研究中，罗宾逊和科尔布[2，3]证明了持久的增加伏隔核[NAC]和内侧前额叶皮层的突触（即树突状脊柱）密度[MPFC]）在行为敏化可卡因方案之后的啮齿动物。他们的发现令人信服，建议重要的病理生理机制 - 异常结构突触可塑性 - 可卡因可能产生了慢性的，顽固的行为（例如，渴望，强迫使用和救济），因此似乎很难在患有这种疾病的人中有线。我们的小组已经开发了一种新颖的放射性示踪剂，11c-ucb - j，用于成像活着的人脑中的突触密度使用正电子 - 发射断层扫描（PET）[62，63]。这是当前的尖端基础研究奖（CEBRA）/R21应用程序旨在应用这种突破方法来探讨是否观察在可卡因依赖性（CD）人类中，将啮齿动物的NAC和MPFC的突触密度增加。如果实现了，当前的研究将产生重大影响，从而提供强大的临床支持 - 对突触水平上的异常大脑结构，为未来的研究奠定了阶段与吸收/节制，与可卡因相关的行为和临床结果的异常突触密度。