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

可卡因使用障碍中异常的突触可塑性：11C UCB J PET 研究

• 批准号: 10614579
• 负责人: GUSTAVO Adolfo ANGARITA
• 金额: $ 72.95万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614579
• 关键词: Abstinence; Admission activity; Affect; Age; Alcohol consumption; Animals; Anterior; Award; Basic Science; Behavior; Binding; Brain; Chronic; Clinical; Cocaine; Cocaine Users; Cocaine use disorder; Data; Decision Making; Dendritic Spines; Development; Disease; Drug abuse; Drug usage; Exploratory/Developmental Grant; Exposure to; Frequencies; Glycoproteins; Hospitals; Hour; Human; Image; Impairment; Individual; Inpatients; Intoxication; Measures; Medial; Mediating; Modeling; Monitor; Neurobiology; Neurocognitive; Neurons; Neurosciences Research; Outcome; Outpatients; Pattern; Performance; Pharmaceutical Preparations; Pilot Projects; Plague; Positron-Emission Tomography; Prefrontal Cortex; Principal Investigator; Proteins; Race; Recurrence; Regimen; Regulation; Relapse; Rewards; Rodent; Role; Sample Size; Scanning; Seminal; Specificity; Stimulant; Study Subject; Synapses; Synaptic Vesicles; Synaptic plasticity; Testing; Time; Toxicology; Translations; Urine; behavioral sensitization; cingulate cortex; clinical translation; cocaine use; cohort; craving; density; design; drug abstinence; drug craving; effective therapy; follow-up; nicotine use; novel; preclinical study; presynaptic; prolonged abstinence; radiotracer; sex; synaptic function

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).

抽象的 在近 20 年前的开创性临床前研究中，Robinson & Kolb [1, 2] 证明了持久的 啮齿类动物内侧前额皮质 (mPFC) 突触（树突棘）密度的变化 他们的研究结果表明可卡因的行为敏化疗法具有潜在的重要意义。 病理生理机制——异常的结构突触可塑性——因此可卡因可能产生 慢性的、顽固的行为（例如，渴望、强迫性使用和复发）看似“与生俱来” 患有这种疾病的人。 我们小组开发了一种新型放射性示踪剂 11C-UCB-J，用于突触密度成像（即突触 使用正电子发射在活体人脑中检测囊泡糖蛋白 2A 型或 SV2A 可用性） 断层扫描 (PET) [3, 4] 根据尖端基础研究奖收集的试点数据。 我们相信，(CEBRA)/R21 机制非常引人注目，并为以下方面提供了第一个翻译支持：1) 患有 CUD 的个体 mPFC 中的突触密度改变（即降低），并且 2) 呈正向 与最近使用可卡因的频率（每月天数）相关，并且 3) 与 可卡因戒断持续时间（自上次使用以来的天数），这些数据表明了一个动态模型。 突触可塑性，其中 SV2A 的可用性通过反复使用可卡因而“正常化”，只会返回到 持续戒毒期间的异常（即低）水平。 当前的 R01 申请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）更大的群体 40 个 CUD 和 40 个匹配的 HC 受试者使用单次扫描，组间设计，与目标 2) 相同 40 名 CUD 受试者使用纵向两次扫描（基线/禁欲前与住院 3 周） 禁欲）受试者内设计。 如果得到证实，当前的研究将产生潜在的重大影响，提供强大的临床 对 CUD 异常突触可塑性假说的翻译支持，推进了我们的研究 对 CUD 中药物引起的突触功能变化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 关于突触营养机制）。