PET imaging of dynorphin/kappa-opioid reactivity to stress in depression

抑郁症中强啡肽/卡帕阿片类药物对应激反应的 PET 成像

• 批准号: 10705218
• 负责人: Elizabeth Adams Bartlett
• 金额: $ 18.13万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705218
• 关键词: Acceleration; Addictive Behavior; Adrenal Glands; Agonist; Anhedonia; Anterior; Anxiety; Autopsy; Award; Biological; Biology; Biomedical Engineering; Brain; Brain imaging; Brain region; Brain scan; Cellular Phone; Characteristics; Clinic; DSM-V; Depressed mood; Development; Diagnosis; Disease remission; Drug Targeting; Dynorphins; Ecological momentary assessment; Exhibits; Functional disorder; Goals; Human; Hydrocortisone; Hypothalamic structure; Image; Individual; Intervention; Laboratories; Life; Life Stress; Link; MRI Scans; Magnetic Resonance Imaging; Major Depressive Disorder; Measurable; Measures; Mediating; Mental Depression; Mental disorders; Mood Disorders; Neurobiology; Opioid Receptor Binding; Outcome Study; Participant; Pathogenesis; Peripheral; Physiological; Pilot Projects; Pituitary Gland; Positron-Emission Tomography; Principal Investigator; Process; Regulation; Reporting; Research; Rest; Rodent; Role; Sensitivity and Specificity; Severities; Standardization; Stress; Structure; Testing; Thick; Tracer; Training; Work; biological adaptation to stress; depressive symptoms; design; disability; drug development; dysphoria; efficacious treatment; follow-up; hypothalamic-pituitary-adrenal axis; improved; in vivo; in vivo monitoring; innovation; investigator training; kappa opioid receptors; multimodal neuroimaging; neural; neural correlate; neurobiological mechanism; personalized medicine; pre-clinical; programs; prospective; psychologic; research study; response; single episode major depressive disorder; skills; social; stress reactivity; stressor; symptomatology; therapeutic target; trait; transmission process

PROJECT SUMMARY/ABSTRACT: Major depressive disorder (MDD) is a leading cause of disability worldwide with a paucity of personalized, efficacious treatments. Life stressors have long been shown to potently predict depressive symptomatology and onset of major depressive episodes. Despite this, the neurobiological mechanisms underlying stress regulation in depression are not yet fully understood in humans. Preclinical and initial human studies implicate kappa-opioid receptor (KOR) deficits in the pathogenesis of MDD and suggest that stress reactivity might contribute to these KOR deficits. The innovative study proposed in this K01 represents a first step to determine if KOR binding deficits and heightened dynorphin/KOR-mediated stress reactivity are observed in MDD relative to healthy controls (HCs). If shown to be so, then the second step will be to determine whether these deficits represent a state effect that it is present in currently depressed and not in euthymic subjects with MDD or a trait effect present in both currently depressed and remitted MDD (to be tested in a follow-up R01). Therefore, we seek to evaluate KOR binding at rest and endogenous dynorphin release to a laboratory stressor in unmedicated, currently depressed participants with MDD vs. HCs. KOR binding and dynorphin release will be quantified in vivo in humans with functional positron emission tomography (PET) with the new tracer [11C]EKAP, already reliably synthesized and used in rodents at the Columbia PET Center, that targets KOR with high sensitivity and specificity. A brief, validated stress task with physiologic and psychologic components will be given during the PET scan that elicits hypothalamic-pituitary-adrenal (HPA) axis activation. Physiologic markers of HPA activation will be acquired proximal to the task, e.g., cortisol, to be compared with KOR binding at rest and stress-induced endogenous dynorphin release in MDD vs. HCs. Further, the Principal Investigator’s (PI) preliminary studies suggest that smartphone-administered ecological momentary assessment (EMA) of daily stressors is greater in depressed relative to control participants and has distinct structural and functional neural correlates. In this study, EMA of daily stressors will be acquired and evaluated to determine if daily stress preceding the PET scan, as well as preceding a structural magnetic resonance imaging (MRI) scan, modulate brain structure, KOR binding, and stress-induced endogenous dynorphin release in depression. This will be the first study to investigate KOR’s role in stress-reactivity in vivo in MDD, and will combine multimodal neuroimaging, peripheral markers of HPA activation, and EMA daily stress. Regardless of the outcome of this study, it will increase our understanding of KOR’s role in MDD and in dysregulated stress reactivity in MDD, potentially suggesting KOR-regulated, stress-sensitive depression subtypes. This award will measurably advance the PI’s training in conducting highly impactful research studies and understanding the neurobiology of mood disorders. This will propel the PI toward research independence, launching her research program aimed at elucidating the consequences of stress in mood disorders and developing interventions to mitigate them.

项目总结/摘要：重度抑郁症（MDD）是全球残疾的主要原因 缺乏个性化的有效治疗。长期以来，生活压力源被证明可以有效地预测 抑郁症和严重抑郁发作的发病。尽管如此，神经生物学 抑郁症的压力调节机制在人类中尚未完全了解。临床前和 最初的人类研究表明，在MDD的发病机制中存在κ-阿片受体（KOR）缺陷，并提示 应激反应可能导致KOR不足。本K 01中提出的创新研究代表了 第一步是确定KOR结合缺陷和强啡肽/KOR介导的应激反应性升高是否 在MDD中观察到相对于健康对照（HC）。如果确实如此，那么第二步将是确定 这些缺陷是否代表了一种状态效应，即它存在于当前抑郁而不是正常情绪中， 患有MDD的受试者或目前抑郁和缓解的MDD中存在的特质效应（将在 后续R 01）。因此，我们试图评估静息时KOR结合和内源性强啡肽释放， 实验室压力源在未用药，目前抑郁的参与者与MDD与HC。KOR结合， 强啡肽释放将在人体内用功能性正电子发射断层扫描（PET）定量， 新的示踪剂[11 C]EKAP已经在哥伦比亚PET中心可靠地合成并用于啮齿动物， 以高灵敏度和特异性靶向KOR。一个简短的，经过验证的压力任务， 在PET扫描期间将给予增强下丘脑-垂体-肾上腺（HPA）轴激活的成分。 HPA激活的生理标志物将在任务附近采集，例如，皮质醇，与 MDD与HC中静息和应激诱导的内源性强啡肽释放的KOR结合。此外，校长 研究者（PI）的初步研究表明，智能手机管理的生态瞬时评估 (EMA)相对于对照组参与者，抑郁症患者的日常压力源更大，并且具有不同的结构性和 功能性神经相关物在这项研究中，将获得和评估日常压力源的EMA，以确定是否 在PET扫描之前，以及在结构磁共振成像（MRI）扫描之前， 调节脑结构，KOR结合，和应激诱导的内源性强啡肽释放抑郁症。这 将是第一个研究KOR在MDD体内应激反应中的作用，并将联合收割机多模式 神经影像学、HPA激活的外周标志物和EMA日常应激。不管结果如何 这项研究将增加我们对KOR在MDD中的作用以及MDD中应激反应失调的理解， 这可能表明KOR调节的压力敏感型抑郁亚型。该奖项将可衡量 推进PI在进行高度影响力的研究和理解神经生物学方面的培训， 情绪障碍这将推动PI走向研究独立，启动她的研究计划， 在阐明情绪障碍中压力的后果和开发干预措施以减轻它们方面。