Aberrant Synaptic Plasticity in Cocaine Use Disorder: A 11C UCB J PET Study

摘要 在近20年前的开创性临床前研究中，罗宾逊和科尔布[1，2]证明了持久的 啮齿类动物内侧前额叶皮层（mPFC）突触（树突棘）密度的变化 可卡因的行为致敏疗法他们的发现表明， 病理生理机制-异常的结构突触可塑性-可卡因可能产生 慢性的、不情愿的行为（例如，渴望、强迫性使用和复发）如此看似“硬连线” 在那些患有这种疾病的人身上。 我们的小组已经开发了一种新的放射性示踪剂，11 C-UCB-J，用于成像突触密度（即，突触 囊泡糖蛋白2A型或SV 2A可用性）在活人脑中的分布 断层扫描（PET）[3，4]。.尖端基础研究奖下收集的试验数据 （CEBRA）/R21机制是令人信服的，我们相信，并提供了第一个翻译支持：1） 改变的（即，较低）CUD个体mPFC中的突触密度，2）阳性 与最近使用可卡因的频率（每月天数）相关，3）与 可卡因戒断持续时间（自上次使用以来的天数）。总之，这些数据表明了一个动态模型， 突触可塑性，其中SV 2A的可用性通过反复使用可卡因而“正常化”， 异常（即，低）水平持续戒毒期间。 当前的R 01应用程序建议复制和扩展这些有希望的初步发现 通过两个实验目标更明确地测试前一个模型：目标1）一个更大的队列， 40名CUD和40名匹配的HC受试者使用单次扫描，组间设计，目标2）相同 40例CUD受试者使用纵向双扫描（基线/戒断前vs.住院3周 禁欲）受试者内设计。 如果得到证实，目前的研究将产生潜在的重大影响，提供强大的临床- 翻译支持异常突触可塑性假说的CUD，推进我们的研究。 对药物诱导的突触功能变化在CUD中的作用的神经生物学理解，以及 最终，鼓励开发更有效的CUD治疗方法（例如，基于以下的那些 突触营养机制）。

Abstract In seminal preclinical studies nearly 20 years ago, Robinson & Kolb [1, 2] demonstrated enduring changes in synaptic (dendritic spine) density in medial prefrontal cortex (mPFC) of rodents following behaviorally sensitizing regimens of cocaine. Their findings suggested a potentially 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 (i.e., synaptic vesicle glycoprotein type 2A or SV2A availability) in the living human brain using positron emission tomography (PET) [3, 4]. . Pilot data collected under the Cutting Edge Basic Research Award (CEBRA)/R21 mechanism are compelling, we believe, and provide the first translation support for: 1) altered (i.e., lower) synaptic density in the mPFC of individuals with CUD that is both 2) positively correlated with the frequency (days per month) of recent cocaine use, and 3) negatively correlated with duration of cocaine abstinence (days since last use). Together, these data suggest a dynamic model of synaptic plasticity in which SV2A availability is “normalized” by recurrent cocaine use, only to return to abnormal (i.e., low) levels during periods of sustained drug abstinence. The current R01 application proposes to replicate and extend these promising preliminary findings and more definitively test the former model through two experimental aims: Aim 1) a larger cohort of 40 CUD and 40 matched HC subjects using a single-scan, between group design, and Aim 2) the same 40 CUD subjects using a longitudinal, two-scan (baseline/pre-abstinence vs. 3 weeks of in-hospital abstinence) within-subject design. If confirmed, the current study would have a potentially major impact, providing powerful clinical- translational support for the aberrant synaptic plasticity hypothesis of CUD, advancing our neurobiological understanding of the role of drug-induced changes in synaptic function in CUD, and ultimately, encouraging the development of more effective treatments for CUD (e.g., those based on synaptotrophic mechanisms).