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).

摘要