Influence of 5-HT1b Activation on the Abuse Related Effects of Cocaine

5-HT1b 激活对可卡因滥用相关影响的影响

• 批准号: 10457811
• 负责人: William Walton Stoops
• 金额: $ 66.01万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457811
• 关键词: Abstinence; Admission activity; Agonist; American; Area; Attenuated; Autoreceptors; Basic Science; Behavior; Characteristics; Clinical; Cocaine; Cocaine Dependence; Cocaine Users; Cocaine use disorder; Cues; Data; Decision Making; Disinhibition; Dose; Double-Blind Method; Enrollment; Goals; Human; Impulsivity; Inpatients; Intravenous; Laboratories; Literature; Maintenance; Measures; Mediating; Migraine; Motivation; Nerve Endings; Neurobiology; Neurosciences; Neurosciences Research; Oral; Outcome; Pharmaceutical Preparations; Pharmacodynamics; Placebo Control; Play; Population; Pre-Clinical Model; Psychological reinforcement; Public Health; Reinforcement Schedule; Research; Research Personnel; Role; Sampling; Schedule; Self Administration; Serotonergic System; Serotonin; Serotonin Receptor 5-HT1B; Short-Term Memory; Sucrose; Synapses; System; Time; Translating; Translations; Underserved Population; base; cocaine overdose; cocaine self-administration; cocaine use; craving; design; diagnostic criteria; discounting; experience; experimental study; human subject; inattention; meetings; neurotransmitter release; non-drug; pre-clinical; pre-clinical research; preclinical study; receptor; reinforcer; reuptake; serotonin receptor; zolmitriptan

ABSTRACT Cocaine use disorder continues to be a significant public health concern. Despite 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 to guide treatment based on those clinical neuroscience findings. Cocaine potently inhibits the reuptake of serotonin (5-HT). Increased synaptic 5- HT resulting from this reuptake inhibition activates multiple 5-HT receptor subtypes. Some of these receptor subtypes have been implicated in the abuse-related effects of cocaine, including its primary reinforcing effects (i.e., cocaine taking behavior). 5-HT1b receptors play a particularly important role in cocaine effects, likely because they are highly expressed in the mesocorticolimbic system. Preclinical data show that zolmitriptan, a commercially available selective 5-HT1b agonist migraine medication approved for human use, selectively attenuates the reinforcing and other abuse-related effects of cocaine. The overarching goal of this project is to advance these promising preclinical findings into clinical populations, thereby demonstrating that the 5-HT1b system plays a key role in the effects of cocaine in humans. To this end, 20 non-treatment seeking human subjects meeting diagnostic criteria for cocaine use disorder will sample doses of intravenous cocaine (0, 10 and 30 mg/70 kg) in experimental sessions after 3 days of maintenance on oral zolmitriptan (0, 2.5, 5 and 10 mg). A placebo-controlled, double-blind, within-subjects design will be used such that all subjects experience all dose conditions in random order. The study will require an approximately 1-month admission to our inpatient unit. After sampling a cocaine dose, subjects will make nine choices between that dose and an alternative reinforcer (US$6.00) on a concurrent progressive-ratio choice task that was developed and validated in our laboratory. A battery of subjective drug-effect measures and tasks that assess distinct domains of impulsivity will be completed during the same experimental sessions in which cocaine choice is assessed. The research proposed here will directly translate findings from preclinical research and provide the initial clinical evidence that 5-HT1b activation, achieved through administration of zolmitriptan, reduces the reinforcing and other abuse-related effects of cocaine, as well as cocaine-associated impulsivity. This study will also provide basic science information about the serotonergic mechanisms underlying the pharmacodynamic effects of cocaine in humans. As such, the outcomes will advance our understanding of the clinical neurobiology of cocaine addiction.

抽象的 可卡因使用障碍仍然是一个重大的公共卫生问题。尽管我们的理解取得了长足进步 临床前模型中可卡因成瘾的神经生物学基础，研究数量有限 已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至关重要 导致可卡因使用障碍所造成问题的回路，并根据这些回路指导治疗 临床神经科学发现。可卡因有效抑制血清素 (5-HT) 的再摄取。突触增加 5- 这种再摄取抑制产生的 HT 会激活多种 5-HT 受体亚型。其中一些受体 亚型与可卡因滥用相关的影响有关，包括其主要的强化作用 （即吸食可卡因的行为）。 5-HT1b 受体在可卡因作用中发挥着特别重要的作用，可能 因为它们在中皮质边缘系统中高度表达。临床前数据显示，佐米曲普坦 批准用于人类使用的市售选择性 5-HT1b 激动剂偏头痛药物，选择性 减弱可卡因的强化作用和其他与滥用相关的作用。该项目的总体目标是 将这些有希望的临床前研究结果推进到临床人群中，从而证明 5-HT1b 系统在可卡因对人类的影响中发挥着关键作用。为此，20名未寻求治疗的人类 符合可卡因使用障碍诊断标准的受试者将采样静脉注射可卡因的剂量（0、10 和 30 mg/70 kg）在口服佐米曲普坦维持 3 天（0、2.5、5 和 10 毫克）。将使用安慰剂对照、双盲、受试者内设计，以便所有受试者都体验到 所有剂量条件均按随机顺序排列。该研究需要我们住院大约 1 个月的时间 单元。在取样可卡因剂量后，受试者将在该剂量和替代剂量之间做出九种选择 强化剂（6.00 美元）用于并行渐进比例选择任务，该任务是在我们的项目中开发和验证的 实验室。一系列主观药物效应测量和任务，用于评估不同的冲动领域 将在评估可卡因选择的相同实验期间完成。研究 这里提出的将直接转化临床前研究的结果并提供初步的临床证据 通过给予佐米曲普坦实现 5-HT1b 激活，减少强化和其他作用 可卡因滥用相关的影响，以及可卡因相关的冲动。这项研究还将提供基本 关于可卡因药效作用背后的血清素机制的科学信息 人类。因此，研究结果将增进我们对可卡因临床神经生物学的理解 瘾。