DOPAMINE REUPTAKE INHIBITORS FOR COCAINE ABUSE

可卡因是一种被广泛滥用的兴奋剂， 主要通过多巴胺系统发挥作用。 然而，没有有效的 药物疗法已经被开发用于治疗可卡因滥用。 此外，委员会认为， 虽然一些实验室研究已经调查了急性行为 可卡因和可能的治疗之间的生理相互作用 在人类中，很少有人研究可卡因的影响， 以及在长期给予治疗药物期间。 在 此外，这些研究有几个局限性，包括评估 治疗药物的剂量范围过窄-这不会导致 关于更高剂量可卡因的潜在安全风险的信息 吸毒成瘾者在更高的风险复发可卡因使用-和管理 以受试者不耐受的方式给药。 因此，主要 该项目的目的是评估行为和生理影响 可卡因在人类之前和期间的长期管理， 可能的治疗剂的剂量范围。 考虑到可卡因 增强效应被认为是通过抑制 多巴胺再摄取，该项目将专门检查代理人与 低滥用倾向，即使其影响通常是中介的 通过多巴胺再摄取抑制。 在这个过程中，受试者 接受三个实验阶段，其中可卡因在0，60和120 mg/70 kg，鼻内（i.n.），被管理。 随后，受试者 在四周内接受研究药物治疗， 他们在第一天接受初始剂量;该剂量逐渐增加 直到他们接受方案中规定的最大剂量或 最大耐受剂量 在治疗期间，以预定剂量 在诱导阶段，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。 在最大维持剂量下三天后，受试者经历三次 更多的实验性会议 当所有会话完成后， 受试者停止服用研究药物。 在一系列的三个 实验中，可卡因的影响将被检查之前和期间， 长期施用多巴胺再摄取阻断剂如马吲哚， 安非他酮或3b-（4-碘苯基）托烷-2b-羧酸甲酯（CIT）。 在每一个实验阶段，将采取以下措施 评估：1）自我报告的影响，作为传统的虐待措施 责任; 2）绩效效应，作为协调的衡量标准， 反应时间和认知障碍; 3）生理影响，如 毒性的量度;和4）药理作用，如通过以下测定的： 血浆可卡因水平随时间的变化和尿代谢物的测量 作为药代动力学特征和/或药物相互作用的量度。 这些 措施将提供一个广泛的行为概况，以比较程度， 其他多巴胺再摄取抑制剂改变可卡因的效果。 这些 研究将是非常宝贵的，以确定是否一个特定的代理人， 适用于在较高剂量下作为可能的治疗剂进行试验， 可卡因滥用的临床试验

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.