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，Robinson&Kolb[1，2]证明了 大鼠内侧前额叶皮质突触(树突棘)密度的变化 可卡因的行为致敏疗法。他们的发现提出了一个潜在的重要问题 病理生理机制--异常的结构突触可塑性--从而产生可卡因 长期的、顽固的行为(例如，渴求、强迫使用和复发)看起来是如此的顽固 在那些患有这种疾病的人身上。 我们团队已经开发了一种新的放射性示踪剂11C-UCB-J，用于成像突触密度(即突触 活体人脑中囊泡糖蛋白(2A型或SV2A型)的正电子发射研究 断层扫描(PET)[3，4]。。在尖端基础研究奖下收集的试点数据 (CEBRA)/R21机制令人信服，我们相信，并为以下方面提供了第一个翻译支持：1) CUD患者mPFC内突触密度改变(即降低)2)均为阳性 与最近使用可卡因的频率(每月天数)相关，以及3)与 可卡因戒断持续时间(自上次使用以来的天数)。总而言之，这些数据表明了一个动态模型 突触可塑性，在这种情况下，SV2A的可用性因反复使用可卡因而“正常化”，但只恢复到 持续戒毒期间的异常(即低)水平。 当前的R01应用程序建议复制和扩展这些有希望的初步发现 并通过两个实验目标更明确地测试前一个模型：目标1)更大的队列 在分组设计和目标之间，使用单次扫描的40名CUD和40名匹配的HC受试者2)相同 40名CUD受试者进行两次纵向扫描(基线/戒断前与住院3周对比 节制)主体内的设计。 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- 对CUD异常突触可塑性假设的翻译支持，推动了我们的 药物诱导的突触功能改变在CUD中作用的神经生物学理解 最终，鼓励开发更有效的慢性阻塞性肺病治疗方法(例如，基于 关于突触营养机制)。

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).