Influence of Orexin Antagonism on Motivation for Cocaine

食欲素拮抗作用对可卡因动机的影响

• 批准号: 9919535
• 负责人: William Walton Stoops
• 金额: $ 55.6万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919535
• 关键词: Adaptive Behaviors; American; Animals; Area; Attenuated; Basic Science; Behavior; Clinical; Cocaine; Cocaine Dependence; Cocaine Users; Cues; Diagnostic; Disease; Dopamine; Dose; Double-Blind Method; Eating; Genetic; Goals; Human; Hypothalamic structure; Impulsivity; Intake; Intravenous; Knock-out; Laboratories; Lateral; Literature; Locomotion; Maintenance; Measures; Motivation; Neurobiology; Neuropeptides; Neurosciences; Neurosciences Research; Oral; Outcome; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Placebos; Play; Population; Pre-Clinical Model; Public Health; Reporting; Research; Rewards; Role; Sampling; Schedule; Self Administration; Short-Term Memory; Signal Transduction; System; Time; Translating; Translations; Visual; Water consumption; Work; addiction; analog; attentional bias; base; cocaine overdose; cocaine use; cognitive task; conditioned place preference; design; drug of abuse; experience; genetic manipulation; human subject; hypocretin; interest; knock-down; meetings; men; non-drug; opioid overdose; pre-clinical; pre-clinical research; preclinical study; receptor; reinforcer; response; sleep regulation; transmission process

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.

抽象的 可卡因使用障碍仍然是一个重大的公共卫生问题。尽管我们大步向前 了解临床前模型中可卡因成瘾的神经生物学基础，数量有限 研究将这些发现转化为临床人群。这种翻译对于识别 神经生物学回路有助于可卡因使用障碍和指导治疗所假定的问题 基于那些临床神经科学发现。对临床前研究的强烈兴趣的领域是 成瘾中的Orexin（也称为降钙素）系统。通过外丘脑的传播，Orexin 系统在适应不良奖励等滥用药物等不良适应性奖励的动机中起着关键作用。奥列生酸的对抗 系统减弱了可卡因的动力，可卡因摄入量的升级和恢复可卡因寻求 行为。第一个也是唯一临床上可用的Orexin拮抗剂Suvorexant（Belsomra®），可减弱 可卡因和可卡因条件的偏好的动机，以及与可卡因相关的冲动 在非人类动物中做出反应。甲脱甲蛋白拮抗通常不会改变食物或食物等适应性行为 进水，也不会改变可卡因引起的运动。总之，这些临床前发现 建议OREXIN系统的拮抗作用有选择地减少可卡因的动机以及其他 不良适应可卡因相关的行为。尽管有强大的临床前文献支持这样的前提 Orexin拮抗作用会减轻可卡因的动机，以及可卡因其他与滥用相关的影响 人类仍未研究区域。该项目的总体目标是翻译有希望的临床前 对临床人群的发现，从而表明Orexin System在动机中起关键作用 对于人类可卡因。为此，寻求人类受试者的非治疗符合诊断标准 可卡因的使用障碍将在维持后的实验会话中采样静脉可卡因剂量 在一系列口服suvorexant剂量上。将使用安慰剂对照，双盲的主体内设计 使所有受试者都以随机顺序经历所有剂量条件。采样可卡因剂量后，受试者 将在同时进行的渐进率选择上进行该剂量和替代增强器之间做出选择 在我们的实验室中开发和验证的任务。同时进行的渐进比例时间表的使用 药物和非毒品增强剂的可用性将允许对奥雷蛋白的相对影响做出推论 对获得这两种增强剂的动机的对抗。一系列主观药物效应措施 并且还将完成认知任务，以评估Orexin拮抗作用如何影响其他可卡因 - 人类的相关结果。这项研究将转化临床前研究的发现，并提供 Orexin拮抗作用减少可卡因的动机以及其他可卡因相关的初始证据 活跃的可卡因用户的适应不良行为。拟议的工作旨在扩大当前的范围 临床神经科学研究可卡因成瘾，专注于奥甲蛋白。