Influence of Orexin Antagonism on Motivation for Cocaine

摘要 可卡因使用障碍仍然是一个重大的公共卫生问题。尽管我们的经济取得了长足进步 在临床前模型中了解可卡因成瘾的神经生物学基础，数量有限 研究小组已经将这些发现转化为临床人群。这样的翻译对于识别 导致可卡因使用障碍和指导治疗问题的神经生物回路 基于那些临床神经科学的发现。临床前研究中最感兴趣的一个领域是 成瘾中的食欲素(也称为下丘脑泌素)系统。通过下丘脑外传递，食欲素 制度在像滥用药物这样的不适应奖励的动机中起着关键作用。食欲素的拮抗作用 系统削弱了可卡因的动机，可卡因摄入量的增加和寻求可卡因的恢复 行为。第一种也是唯一一种临床上可用的食欲素拮抗剂，Suvorexant(BelSomra®)，可以减弱 可卡因和可卡因条件性地点偏爱的动机以及可卡因相关的冲动 在非人类动物身上做出反应。食欲素拮抗一般不会改变适应行为，如食物或 水的摄入，也不会改变可卡因诱导的运动。综上所述，这些临床前发现 提示食欲素系统拮抗剂选择性地降低可卡因的动机，以及其他 适应不良的可卡因相关行为。尽管一本强有力的临床前文献支持这样的假设 食欲素拮抗剂减弱了可卡因的动机，以及可卡因的其他与滥用有关的影响，这 在人类身上，这一区域仍未得到研究。该项目的首要目标是将前景看好的临床前 在临床人群中的研究结果，从而证明食欲素系统在动机中发挥关键作用 在人类身上发现可卡因。为此，没有寻求治疗的人类受试者符合诊断标准 可卡因使用障碍将在维持后的实验阶段对静脉注射的可卡因剂量进行抽样 在一系列口服超排氧剂剂量上。将使用安慰剂对照、双盲、受试者内设计。 使得所有受试者以随机顺序经历所有剂量条件。在采集了一定剂量的可卡因后，受试者 将在该剂量和替代增强剂之间做出选择，同时进行累进比选择 任务是在我们的实验室开发和验证的。并行累进比率时间表的使用 药物和非药物增强剂的可用性将允许对增食欲素的相对影响做出推断 对获得这两种增强剂的动机的对抗。一系列主观的药效测量方法 认知任务也将完成，以评估食欲素拮抗如何影响其他可卡因- 在人类身上的相关结果。这项研究将转化临床前研究的结果，并提供 初步证据表明，食欲素拮抗剂降低了可卡因以及其他与可卡因相关的动机 活跃的可卡因吸毒者的不良适应行为。拟议的工作旨在扩大目前 以食欲素为中心的可卡因成瘾的临床神经科学研究。

ABSTRACT Cocaine use disorder continues to be a significant public health concern. Despite great strides in our understanding of the neurobiological underpinnings of cocaine addiction in preclinical models, a limited amount of research has translated those findings into clinical populations. Such translation is crucial to identify neurobiological circuits that contribute to the problems posed by cocaine use disorder and guide treatment based on those clinical neuroscience findings. One area of intense interest in preclinical research is the role of the orexin (also known as hypocretin) system in addiction. Through extrahypothalamic transmission, the orexin system plays a key part in motivation for maladaptive rewards like drugs of abuse. Antagonism of the orexin system attenuates motivation for cocaine, escalation of cocaine intake and reinstatement of cocaine seeking behavior. The first and only clinically available orexin antagonist, suvorexant (Belsomra®), attenuates motivation for cocaine and cocaine conditioned place preference, as well as cocaine-associated impulsive responding in non-human animals. Orexin antagonism generally does not alter adaptive behaviors like food or water intake, nor does it change cocaine-induced locomotion. Taken together, these preclinical findings suggest that orexin system antagonism selectively reduces motivation for cocaine, as well as other maladaptive cocaine-associated behaviors. Although a robust preclinical literature supports the premise that orexin antagonism attenuates motivation for cocaine, along with cocaine’s other abuse-related effects, this area remains unstudied in humans. The overarching goal of this project is to translate promising preclinical findings into clinical populations, thereby demonstrating that the orexin system plays a key role in motivation for cocaine in humans. To this end, non-treatment seeking human subjects meeting diagnostic criteria for cocaine use disorder will sample doses of intravenous cocaine in experimental sessions following maintenance on a range of oral suvorexant doses. A placebo-controlled, double-blind, within-subjects design will be used such that all subjects experience all dose conditions in random order. After sampling a cocaine dose, subjects will make choices between that dose and an alternative reinforcer on a concurrent progressive-ratio choice task that was developed and validated in our laboratory. The use of concurrent progressive-ratio schedules of drug and non-drug reinforcer availability will allow inferences to be made about the relative influence of orexin antagonism on motivation to obtain these two types of reinforcers. A battery of subjective drug-effect measures and cognitive tasks will also be completed to evaluate how orexin antagonism influences other cocaine- associated outcomes in humans. This research will translate findings from preclinical research and provide the initial evidence that orexin antagonism reduces motivation for cocaine, as well as other cocaine-associated maladaptive behaviors in active cocaine users. The proposed work seeks to expand the scope of current clinical neuroscience research on cocaine addiction by focusing on orexin.