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

摘要 可卡因使用障碍仍然是一个重大的公共卫生问题。尽管我们在理解 关于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 已经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上的 导致可卡因使用障碍所造成的问题的电路，并根据这些电路指导治疗 临床神经科学发现。强力抑制血清素（5-HT）的再摄取。增加突触5- 由这种再摄取抑制引起的HT激活多种5-HT受体亚型。其中一些受体 亚型与可卡因的滥用相关作用有关，包括其主要的强化作用 (i.e.,可卡因服用行为）。5-HT 1b受体在可卡因的作用中起着特别重要的作用， 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坦， 市售的选择性5-HT 1b激动剂偏头痛药物， 减弱可卡因的强化作用和其他与滥用有关的作用。该项目的总体目标是 将这些有希望的临床前发现推进到临床人群中，从而证明5-HT 1b 系统在可卡因对人体的影响中起着关键作用。为此，20名不寻求治疗的人 符合可卡因使用障碍诊断标准的受试者将取样静脉内可卡因剂量（0，10 和30 mg/70 kg），口服佐米曲坦（0、2.5、5和10 mg）。将使用安慰剂对照、双盲、受试者内设计，以便所有受试者均经历 所有剂量条件均为随机顺序。本研究将需要大约1个月的住院时间 单位在抽取一个可卡因剂量后，受试者将在该剂量和另一种剂量之间做出九个选择 在我们的研究中开发和验证的并行渐进比率选择任务上， 实验室一组主观药物效应测量和任务，评估冲动的不同领域 将在评估可卡因选择的同一实验阶段完成。研究 本文提出的方法将直接转化临床前研究的结果，并提供初步的临床证据 通过给予佐米曲坦实现的5-HT 1b激活， 可卡因的滥用相关影响以及可卡因相关冲动。这项研究还将提供基本的 关于可卡因药效学作用背后的可卡因能机制的科学信息， 人类因此，这些结果将促进我们对可卡因临床神经生物学的理解。 成瘾

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.