Targeting orexin to treat nicotine dependence

摘要 尼古丁依赖是一种流行且代价高昂的公共卫生流行病。虽然存在几种治疗选择， 大多数试图戒烟的人最终会复发，即使使用目前可用的戒烟方法， 艾滋病因此，需要具有新作用机制的药物来提高戒烟率。为 例如，汇集的临床前证据表明，食欲素拮抗剂具有治疗 成瘾当前的R 03应用程序将通过以下方式将这些临床前发现转化为临床领域： 向尼古丁依赖性吸烟者施用FDA批准的食欲素拮抗剂苏沃雷生。鉴于 在临床前模型中，食欲素拮抗作用减弱了获得滥用物质的动机，我们假设 在吸烟者身上也有类似的效果。具体而言，苏沃雷生将以剂量依赖性方式给药 采用双盲、安慰剂对照、交叉设计。食欲素拮抗作用对吸烟提示的影响- 将测试诱发的渴望和急性吸烟的主观影响。考虑到食欲素和尼古丁 影响多巴胺能信号传导，还将评估更一般的奖赏敏感性。潜在副作用 还将测量与苏沃雷生作为睡眠辅助剂的作用相关的药物浓度。这项工作将提供关键信息， 食欲素在尼古丁依赖中的作用，并将提示食欲素拮抗剂是否可能是一种可行的治疗方法 尼古丁依赖的治疗策略此R 03应用程序将提供必要的试点和可行性数据， 更大的项目，直接评估食欲素拮抗作用对尼古丁依赖性神经生物学的影响， 个体

Abstract Nicotine dependence is a prevalent and costly public health epidemic. While several treatment options exist, the majority of individuals who try to quit will eventually relapse even when using currently available cessation aids. Therefore, medications with novel mechanisms of action are needed to enhance cessation rates. For instance, converging preclinical evidence shows that orexin antagonism has substantial promise for treating addiction. This current R03 application will translate these preclinical findings into the clinical domain by administering the FDA approved orexin antagonist, suvorexant, to nicotine dependent smokers. Given that orexin antagonism blunts the motivation to attain abused substances in preclinical models, we hypothesize to find a similar effect in smokers. Specifically, suvorexant will be administered in a dose dependent manner using a double-blind, placebo controlled, cross over design. The impact of orexin antagonism on smoking cue- induced craving and the subjective effects of acute smoking will be tested. Given that both orexin and nicotine impact dopaminergic signaling, more general reward sensitivity also will be evaluated. Potential side effects related to suvorexant’s action as a sleep aid also will be measured. This work will offer key information on the role of orexin in nicotine dependence and will suggest whether orexin antagonists may be a viable treatment strategy for nicotine dependence. This R03 application will provide pilot and feasibility data necessary for larger projects that directly evaluate the neurobiological impact of orexin antagonism in nicotine dependent individuals.