DOPAMINE REUPTAKE INHIBITORS FOR COCAINE ABUSE

用于可卡因滥用的多巴胺再摄取抑制剂

• 批准号: 6104097
• 负责人: Alison Oliveto
• 金额: $ 11.61万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 1999-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6104097
• 关键词: cocaine; cognition disorders; dopamine agonists; drug abuse; drug abuse chemotherapy; drug screening /evaluation; human subject; human therapy evaluation; pharmacokinetics; psychomotor reaction time

Cocaine, a widely abused stimulant, is thought to produce its reinforcing effects primarily through the dopamine system. Yet no effective pharmacotherapy has been developed for treating cocaine abuse. Moreover, although a few laboratory studies have investigated the acute behavioral and physiological interactions between cocaine and possible treatment agents in humans, fewer still have examined the effects of cocaine prior to and during chronic administration of treatment medications. In addition, these studies have several limitations, including assessing a too narrow dosage range of the treatment medication - which gives no information about the potential safety risk of higher dosages to cocaine addicts at higher risk of relapse to cocaine use - and administering the medication in a manner not tolerated by subjects. Therefore, the major aim of this project is to assess the behavioral and physiological effects of cocaine in humans prior to and during chronic administration of possible treatment agents across a range of doses. Given that cocaine's reinforcing effects are thought to be produced through inhibition of dopamine reuptake, this project specifically will examine agents with low abuse liability, even though their effects generally are mediated through dopamine reuptake inhibition. In this procedure, subjects undergo three experimental sessions in which cocaine at 0, 60, and 120 mg/70 kg, intranasal (i.n.), is administered. Subsequently, subjects are inducted onto the study medication over a four-week period, such that they receive an initial dose on day one; this dose is gradually increased until they receive either the maximal dose defined in the protocol or their maximal tolerated dose. At a predetermined dose during the induction phase, subjects will undergo three experimental sessions to examine the behavioral and physiological response to cocaine or placebo. After three days at the maximal maintenance dose, subjects undergo three more experimental sessions. When all sessions have been completed, subjects are taken off the study medication. In a series of three experiments, the effects of cocaine will be examined prior to and during chronic administration of dopamine reuptake blockers such as mazindol, bupropion, or methyl 3b-(4-iodophenyl)tropane-2b-carboxylate (CIT). During each experimental session, the following measures will be assessed: 1) self-reported effects, as a traditional measure of abuse liability; 2) performance effects, as a measure of coordination, reaction time and cognitive impairments; 3) physiological effects, as a measure of toxicity; and 4) pharmacological effects as determined by plasma cocaine levels over time and measurement of urinary metabolites as a measure of pharmacokinetic profile and/or drug interaction. These measures will provide a wide behavioral profile to compare the degree to which other dopamine reuptake inhibitors alter cocaine's effects. These studies will be invaluable in determining whether a particular agent may be suitable for testing at higher doses as a possible treatment agent for cocaine abuse in a clinical trial.

可卡因是一种广泛滥用的兴奋剂，被认为可以产生增强作用 主要通过多巴胺系统发挥作用。 却还没有见效 已经开发出药物疗法来治疗可卡因滥用。 而且， 尽管一些实验室研究已经调查了急性行为 可卡因与可能的治疗之间的生理相互作用 在人类中，很少有人之前研究过可卡因的影响 长期服用治疗药物期间和期间。 在 此外，这些研究有一些局限性，包括评估 治疗药物的剂量范围太窄 - 没有提供 有关高剂量可卡因潜在安全风险的信息 成瘾者再次吸食可卡因的风险较高 - 以及服用可卡因 以受试者不能耐受的方式用药。 因此，主要 该项目的目的是评估行为和生理影响 长期服用可卡因之前和期间对人体的影响 不同剂量范围内可能的治疗药物。 鉴于可卡因 强化效应被认为是通过抑制 多巴胺再摄取，该项目将专门检查具有 滥用可能性较低，尽管其影响通常是经过调节的 通过抑制多巴胺再摄取。 在此过程中，受试者 进行三个实验，其中可卡因分别为 0、60 和 120 mg/70 kg，鼻内（i.n.）施用。 随后，科目是 在四个星期的时间内引入研究药物，这样 他们在第一天接受初始剂量；这个剂量逐渐增加 直到他们接受方案中定义的最大剂量或 他们的最大耐受剂量。 期间按预定剂量 入门阶段，受试者将经历三个实验阶段 检查对可卡因或安慰剂的行为和生理反应。 在最大维持剂量三天后，受试者接受三 更多实验课程。 当所有会话都完成后， 受试者停止研究药物治疗。 在一系列三 实验之前和期间将检查可卡因的影响 长期服用多巴胺再摄取阻滞剂，例如马吲哚， 安非他酮或 3b-(4-碘苯基)托烷-2b-甲酸甲酯 (CIT)。 在每次实验期间，将采取以下措施 评估：1）自我报告的影响，作为虐待的传统衡量标准 责任; 2）绩效效果，作为协调的衡量标准， 反应时间和认知障碍； 3）生理效应，如 毒性测量； 4) 药理作用测定 随时间变化的血浆可卡因水平和尿代谢物的测量 作为药代动力学特征和/或药物相互作用的测量。 这些 措施将提供广泛的行为概况来比较程度 其他多巴胺再摄取抑制剂会改变可卡因的作用。 这些 研究对于确定特定药物是否可能具有无价的价值 适合以更高剂量进行测试，作为可能的治疗剂 临床试验中的可卡因滥用。