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: 10211330
• 负责人: GUSTAVO Adolfo ANGARITA
• 金额: $ 75.37万
• 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/10211330
• 关键词: Abstinence; Admission activity; Affect; Age; Alcohol consumption; Animals; Anterior; Basic Science; Behavior; Binding; Brain; Chronic; Clinical; Cocaine; Cocaine Users; Data; Decision Making; Dendritic Spines; Development; Disease; Drug abuse; Drug usage; Exploratory/Developmental Grant; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; 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; Structure; Study Subject; Synapses; Synaptic Vesicles; Synaptic plasticity; Testing; Time; Toxicology; Translations; Urine; base; behavioral sensitization; cingulate cortex; cocaine use; cohort; craving; density; design; drug abstinence; drug craving; effective therapy; follow-up; nicotine use; novel; preclinical study; presynaptic; 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 在大约20年前的开创性临床前研究中，鲁滨逊和科尔布[1，2]证明了持久 随后的啮齿动物介质前额叶皮层（MPFC）突触（树突状脊柱）密度的变化 可卡因的行为敏感性方案。他们的发现暗示了潜在的重要 病理生理机制 - 异常结构合成可塑性 - 可卡因可能产生 慢性，顽固的行为（例如，渴望，强迫使用和救济）似乎是“硬连线”的 在患有疾病的人。 我们的小组开发了一种新型的放射性示踪剂11C-UCB-J，用于成像突触密度（即突触 囊泡糖蛋白2a型或SV2A可用性）在活体脑中使用正电子发射 断层扫描（PET）[3，4]。根据尖端基础研究奖收集的飞行员数据 我们相信（CEBRA）/R21机制令人信服，并提供了第一个翻译支持：1） cud的个体的MPFC中改变（即下部）突触密度，这两者均为2） 与最近可卡因使用的频率（每月）相关，3）与 可卡因禁欲的持续时间（自上次使用以来的天数）。这些数据一起提出了一个动态模型 SV2A可用性通过可卡因使用“标准化”的突触可塑性，只是返回 在持续的药物戒酒期间，异常（即低）水平。 当前的R01申请提案复制并扩展这些承诺的初步发现 更明确地通过两个实验目的测试了以前的模型：目标1）较大的队列 40个CUD和40个匹配的HC受试者，使用单扫，在组设计之间和目标2）相同 40个使用纵向的二扫描的受试者（基线/预先排斥与院内3周 禁欲）受试者内部设计。 如果得到确认，当前的研究将产生潜在的重大影响，从而提供强大的临床 - 对CUD的异常合成可塑性假设的转化支持，推进了我们 神经生物学对药物诱导的突触功能变化的作用的理解， 最终，鼓励开发更有效的CUD治疗方法（例如 关于突触营养机制）。