Drug repurposing study for tobacco dependence treatment using zebrafish

描述（由申请人提供）：吸烟是美国发病率、死亡率和医疗费用过高的最重要的可预防原因。药物滥用导致我国每年在可预防的医疗保健费用上花费1370亿美元，其中烟草（960亿美元）占绝大多数。世界卫生组织宣布，与烟草有关的疾病是一种全球流行病，如果势头不减，预计到2030年，全球每年将有800万人死亡。随着药物疗法、伐尼克兰和安非他酮的引入，在治疗烟草依赖患者方面取得了进展。尽管在使患者实现戒烟方面已被证明有效，但大多数患者不能通过这些目前推荐的单一疗法实现长期戒烟。此外，个体对药物治疗的反应存在显著差异。鉴于此，迫切需要额外的药物治疗药物，这些药物可以添加到医生的医疗设备中，用于治疗烟草依赖。我们的临床前斑马鱼在伐尼克兰或安非他酮治疗下的急性尼古丁反应模型为研究可能介导尼古丁反应的现有药物提供了一个新的平台，并可用于治疗烟草依赖。为了实现这一目标，我们将在以下特定目的中使用两种互补的斑马鱼试验：目的1：确定减轻尼古丁诱导的斑马鱼幼虫运动激活的药物。我们的工作假设是现有药物的一个子集，当测试时将减弱尼古丁的运动激活特性，而不会引起全身不适或非尼古丁刺激引起的运动活动丧失。我们将使用斑马鱼幼虫试验系统地评估660种经过医生审查、FDA批准的药物。目的2：确定抑制成年斑马鱼尼古丁诱导的条件位置偏好的药物。我们的工作假设是现有药物的一个子集会干扰尼古丁的奖励特性，从而抑制尼古丁诱导的条件位置偏好（CPP）。我们将使用成年斑马鱼CPP试验系统地评估40种药物。减少尼古丁诱导的幼虫运动的药物将被优先考虑。

DESCRIPTION (provided by applicant): Cigarette smoking is the single most important preventable cause of morbidity, mortality, and excess health care costs in the United States. Substance abuse causes our nation $137 billion annually in preventable health care costs, with tobacco ($96 billion) contributing to the overwhelming majority of this expense. The World Health Organization declared tobacco-related disease a global epidemic, predicted to cause an estimated 8 million annual deaths worldwide by 2030, if unabated. Advancements in the treatment of patients for tobacco dependence have been made with the introduction of pharmacotherapeutics, varenicline and bupropion. Despite proven efficacy in enabling patients to achieve abstinence, most patients do not achieve long-term tobacco abstinence with these currently recommended monotherapies. In addition, significant variation exists in how individuals respond to the drug therapies. Given this, there exists a significant need for additional pharmacotherapeutics that can be added to a physician's armamentarium for use in the treatment of tobacco dependence. Our preclinical zebrafish model for acute nicotine response in the presence of varenicline or bupropion treatment provides a novel platform for studying existing medications that may mediate nicotine response and be repurposed for the treatment of tobacco dependence. To accomplish this, we will use two complementary zebrafish assays in the following Specific Aims: AIM 1: Identify medications that attenuate nicotine-induced locomotor activation in larval zebrafish. Our working hypothesis is a subset of the existing medications when tested will attenuate the locomotor activating properties of nicotine without causing general malaise or loss of locomotor activity induced by non-nicotine stimuli. We will systematically evaluate 660 physician-vetted, FDA approved medications using the larval zebrafish assay. AIM 2: Identify medications that inhibit nicotine-induced conditioned place preference in adult zebrafish. Our working hypothesis is a subset of existing medications will interfere with the rewarding properties of nicotine and thereby inhibit nicotine-induced conditioned place preference (CPP). We will systematically evaluate 40 medications using the adult zebrafish CPP assay. Medications attenuating nicotine-induced larval locomotion will be prioritized.