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

描述(由申请人提供)：可卡因依赖在美国是一个普遍存在的问题，给社会和国家带来了巨大的个人和财政成本。更令人不安的是，最近的一项研究显示，美国可卡因的累计使用率为总人口的16%，即略高于4800万人。到目前为止，没有一种药物治疗可卡因依赖的药物具有FDA对可卡因依赖者的治疗指征。鉴于上述情况的心理社会影响，开发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，5-羟色胺1B(5-HT1B)受体，作为治疗可卡因依赖的可能方法。有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。受体的药理调节导致不同的可卡因使用，5-HT1B基因敲除小鼠对可卡因使用的易感性增加。然而，这些研究的结果并不完全一致。为了阐明这一问题，我们建议使用最先进的分子成像技术和有效的自我给药范式来研究可卡因和5-HT1B受体在可卡因依赖受试者中的关系。我们建议使用新的5-HT1B PET放射性配基[11C]-P943来研究可卡因依赖者和健康对照组的5-HT1B受体结合。我们还将通过在经过充分验证的可卡因自我管理范例中研究受试者，来获得可卡因使用的衡量标准。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名从未使用过非法物质的匹配的健康对照组受试者。所有受试者将用[11C]-P943进行一次PET扫描，以量化皮质和皮质下5-HT1B受体的分布。有可卡因依赖史的受试者也将接受自我给药范例，以获得与使用可卡因的脆弱性有关的参数。我们还将研究5-HT1B受体结合和自身给药范例中的可卡因使用是否相互关联。该项目的成功完成将使进一步研究靶向5-HT1B受体和调节可卡因使用的分子成为可能。与公共健康相关：可卡因依赖在美国是一个普遍存在的问题，给社会和国家带来了巨大的个人和财政成本。由于目前尚无对可卡因依赖者有效的药物治疗方法，本项目将研究特定系统作为管理可卡因依赖者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。

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.