Drug repurposing study for tobacco dependence treatment using zebrafish

说明(申请人提供)：在美国，吸烟是导致发病率、死亡率和医疗费用过高的最重要的可预防原因。药物滥用每年导致我们国家1370亿美元的可预防医疗费用，其中烟草(960亿美元)贡献了这笔费用的绝大多数。世界卫生组织宣布，与烟草相关的疾病是一种全球流行病，预计到2030年，如果不减少的话，每年将导致全球800万人死亡。随着药物疗法、伐伦克林和安非他酮的引入，烟草依赖患者的治疗取得了进展。尽管已证实能使患者实现戒烟的有效性，但大多数患者并不能通过这些目前推荐的单一疗法实现长期戒烟。此外，个体对药物疗法的反应也存在显著差异。有鉴于此，有很大的需要额外的药物疗法，可以添加到内科医生的武器，用于治疗烟草依赖。我们的临床前斑马鱼急性尼古丁反应模型在存在varenicline或安非他酮治疗的情况下，为研究现有药物提供了一个新的平台，这些药物可能介导尼古丁反应并被重新用于烟草依赖的治疗。为了实现这一目标，我们将在以下特定目标中使用两种互补的斑马鱼检测方法：目标1：确定可以减弱尼古丁诱导的斑马鱼幼体运动激活的药物。我们的工作假设是现有药物的子集，当测试时，将减弱尼古丁的运动激活特性，而不会导致全身不适或非尼古丁刺激引起的运动活动丧失。我们将使用幼虫斑马鱼试验系统地评估660种经医生审查、FDA批准的药物。目的2：寻找抑制尼古丁诱导的成年斑马鱼条件性位置偏爱的药物。我们的工作假设是，现有药物的一部分将干扰尼古丁的奖赏特性，从而抑制尼古丁诱导的条件性位置偏爱(CPP)。我们将使用成年斑马鱼CPP试验系统地评估40种药物。减轻尼古丁诱导的幼虫活动的药物将是优先考虑的。

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.