A PET study of 5-HT1B receptor binding as a novel biomarker for cocaine dependenc

5-HT1B 受体结合作为可卡因依赖的新型生物标志物的 PET 研究

• 批准号: 7660275
• 负责人: ROBERT T MALISON
• 金额: $ 21.23万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660275
• 关键词: Acute; Arts; Binding; Biological Markers; Clinical; Cocaine; Cocaine Dependence; Cocaine Users; Corpus striatum structure; Data; Development; Family; Functional disorder; Goals; Human; Incidence; Individual; Infusion procedures; Knockout Mice; Laboratories; Measures; Molecular Target; National Institute of Drug Abuse; Patients; Pattern; Pharmaceutical Preparations; Play; Population; Positron-Emission Tomography; Pre-Clinical Model; Recording of previous events; Recruitment Activity; Regulation; Role; Self Administration; Serotonin; Serotonin Receptor 5-HT1B; Societies; Study Subject; System; United States; base; cocaine use; cohort; combat; cost; interest; molecular imaging; novel; preclinical study; psychosocial; public health relevance; radioligand; receptor; receptor binding

DESCRIPTION (provided by applicant): Cocaine dependence is a widespread problem in the US with a significant personal and fiscal cost to society and the nation. More disturbingly a recent study showed that the cumulative incidence of cocaine use in the United States was 16% of the population or slightly more than 48,000,000 people. To date there are no drug treatments for cocaine dependence that have FDA indications for the treatment of cocaine dependent subjects. Given the psychosocial impact of the condition as described above, the need for the development of novel molecular targets for the treatment of cocaine dependence has never been as acute as it is today. We will study a novel molecular target, the serotonin 1B (5-HT1B) receptor as a possible treatment for cocaine dependence. There are a number of preclinical studies that implicate the 5-HT1B receptor in the pathophysiology of cocaine dependence. Pharmacological modulation of the receptor results in differential cocaine use and 5-HT1B knockout mice have increased vulnerability to cocaine use. However, the results of these studies are not entirely consistent. In order to clarify this issue, we propose to study the relationship between cocaine and 5-HT1B receptor in cocaine dependent subjects using state of the art molecular imaging and a validated self administration paradigm. We propose to use the novel 5-HT1B PET radioligand, [11C]-P943 to study 5-HT1B receptor binding in cocaine dependent subjects compared with healthy control subjects. We will also obtain measures of cocaine use, by studying subjects in a well validated, paradigm of cocaine self administration. In order to do this we will recruit a cohort of 8 subjects with a history of cocaine dependence and 8 matched healthy control subjects who have never used illicit substances. All subjects will have one PET scan with [11C]-P943 to quantify cortical and subcortical 5-HT1B receptor distribution. Subjects with a history of cocaine dependence will also undergo a self administration paradigm to obtain parameters related to vulnerability to use cocaine. We will also study whether 5-HT1B receptor binding and cocaine use in the self administration paradigm are correlated with each other. The successful completion of this project will allow further study of molecules that target the 5-HT1B receptor and modulate cocaine use. PUBLIC HEALTH RELEVANCE: Cocaine dependence is a widespread problem in the US, with a significant personal and fiscal cost to society and the nation. As there are no well validated drug treatments for individuals with cocaine dependence, this project will study the role of a specific system as a possible treatment target for the management of individuals with cocaine dependence. Successful completion of this project will allow for the development of novel treatments to help patients and their families combat this problem.

描述（由申请人提供）：可卡因依赖是美国的一个普遍问题，给社会和国家带来巨大的个人和财政成本。更令人不安的是，最近的一项研究表明，美国吸食可卡因的累积发病率占总人口的 16%，即略高于 48,000,000 人。迄今为止，尚无 FDA 批准用于治疗可卡因依赖受试者的可卡因依赖药物治疗。鉴于上述病症的社会心理影响，开发用于治疗可卡因依赖的新分子靶点的需求从未像今天这样迫切。我们将研究一种新的分子靶点，即血清素 1B (5-HT1B) 受体，作为可卡因依赖的可能治疗方法。许多临床前研究表明 5-HT1B 受体与可卡因依赖的病理生理学有关。受体的药理学调节导致可卡因使用的差异，并且 5-HT1B 敲除小鼠对可卡因使用的脆弱性增加。然而，这些研究的结果并不完全一致。为了澄清这个问题，我们建议使用最先进的分子成像和经过验证的自我给药范例来研究可卡因依赖受试者中可卡因和 5-HT1B 受体之间的关系。我们建议使用新型 5-HT1B PET 放射性配体 [11C]-P943 来研究可卡因依赖受试者与健康对照受试者的 5-HT1B 受体结合情况。我们还将通过在经过充分验证的可卡因自我给药范例中研究受试者来获得可卡因使用的测量结果。为了做到这一点，我们将招募 8 名有可卡因依赖史的受试者和 8 名从未使用过非法药物的匹配健康对照受试者组成的队列。所有受试者均将接受一次 [11C]-P943 PET 扫描，以量化皮质和皮质下 5-HT1B 受体分布。有可卡因依赖史的受试者还将经历自我管理范例，以获得与使用可卡因的脆弱性相关的参数。我们还将研究 5-HT1B 受体结合和自我给药范式中可卡因的使用是否相互相关。该项目的成功完成将有助于进一步研究针对 5-HT1B 受体并调节可卡因使用的分子。公共卫生相关性：可卡因依赖是美国的一个普遍问题，给社会和国家带来巨大的个人和财政成本。由于对于可卡因依赖个体尚无经过充分验证的药物治疗方法，因此该项目将研究特定系统作为可卡因依赖个体管理的可能治疗目标的作用。该项目的成功完成将有助于开发新的治疗方法，帮助患者及其家人应对这一问题。