Evaluation of Novel Treatments for Stimulant Dependence

描述（由申请人提供）：美国最近的调查显示，过去一个月约有260万人报告使用可卡因/快克。尽管一致的研究努力开发有效的药物疗法，但尚未发现广泛有效的疗法。可卡因主要通过与中枢多巴胺通路的相互作用发挥其强化作用，长期使用可卡因会导致这些神经系统的失调。本申请提出通过在人类实验室环境中采用良好控制的实验方法来检查新型药剂阿立哌唑（Abilify）对可卡因的潜在功效。阿立哌唑是在美国上市的最新的非典型抗精神病药;它的神经药理学特征确实是独特的，并使它与所有其他非典型的神经安定药区别开来。阿立哌唑对D2和5-HT 1a受体具有高亲和力，在此作为部分激动剂，对5-HT 2受体具有高亲和力，在此作为拮抗剂。我们假设阿立哌唑既可以阻断可卡因的突触作用，又可以改善长期使用可卡因引起的神经紊乱。健康、成年、可卡因依赖的志愿者（n=36）也吸烟，将作为住院患者入组45天。在短暂的洗脱和单盲安慰剂导入后，他们将在双盲条件下随机分配到3个治疗组之一（0、15或30 mg阿立哌唑口服/天）。将在安慰剂导入期、急性给药期和稳态时进行补体激发试验。在每个阶段，将在可卡因剂量效应激发阶段检查可卡因和阿立哌唑之间的直接药效学和药代动力学相互作用。阿立哌唑治疗对可卡因强化作用的影响将直接通过采用替代药物的自我给药程序进行检查，并已由我们的实验室进行了充分表征。将在与所用药物相关的剂量范围内检查复方甘草酸苷，药效学评估将是多维的，包括主观、客观、生理和行为结果。此外，由于初步数据表明，非典型抗精神病药物可能会减少吸烟，次要目的是直接检查阿立哌唑与安慰剂相比对吸烟行为的影响。这项研究提供了一个独特的机会，检查吸烟的控制条件下，在一段时间的限制，吸烟地形图程序和自然吸烟措施将被采用。总的来说，该项目将探索一种新型药物阿立哌唑治疗可卡因依赖的潜在疗效，同时提供启动门诊临床试验所需的必要安全性数据，并探索这种药物对减少吸烟或戒烟的潜在疗效。

DESCRIPTION (provided by applicant): Recent surveys in the U.S. reveal that about 2.6 million individuals reported use of cocaine/crack in the past month. Despite a concerted research effort to develop an effective pharmacotherapy, no broadly effective therapies have been discovered. Cocaine exerts its reinforcing effects largely through interactions with central dopamine pathways, and chronic use of cocaine leads to dysregulation of these neural systems. This application proposes to examine a novel agent, aripiprazole (Abilify(r)), for its potential efficacy against cocaine by employing well-controlled experimental methods in a human laboratory setting. Aripiprazole is the newest atypical antipsychotic marketed in the U.S.; its neuropharmacological profile is truly unique and sets it apart from all other atypical neuroleptics. Aripiprazole has a high affinity for D2 and 5-HT1a receptors where it acts as a partial agonist, and at 5-HT2 receptors where it acts as an antagonist. We hypothesize that aripiprazole may both block the synaptic effects of cocaine and improve the neural perturbations resulting from chronic cocaine use. Healthy, adult, cocaine-dependent volunteers (n=36) who also smoke cigarettes will be enrolled as inpatients for 45 days. Following a brief wash-out and single-blind placebo lead-in, they will be randomly assigned to 1 of 3 treatment groups (0,15 or 30 mg aripiprazole p.o/day) under double-blind conditions. Cocaine challenge sessions will be conducted during the placebo lead-in, acute dosing phase, and at steady-state. During each phase, the direct pharmacodynamic and pharmacokinetic interaction between cocaine and aripiprazole will be examined in cocaine dose-effect challenge sessions. The effects of aripiprazole treatment on the reinforcing effects of cocaine will be examined directly with a self-administration procedure that employs alternative reinforcers and has been well-characterized by our laboratory. Cocaine will be examined over a range of doses relevant to those used illicitly, and pharmacodynamic assessments will be multi-dimensional, including subjective, objective, physiological and behavioral outcomes. In addition, because preliminary data suggest that atypical antipsychotics may reduce cigarette smoking, a secondary aim is to examine directly the effects of aripiprazole on smoking behavior in comparison to placebo. This study provides a unique opportunity to examine smoking under controlled conditions during a period of confinement; both smoking topography procedures and naturalistic smoking measures will be employed. Overall, this project will explore the potential therapeutic efficacy of a novel agent, aripiprazole, for the treatment of cocaine dependence while simultaneously providing the requisite safety data needed to launch an outpatient clinical trial and exploring the potential efficacy of this agent for smoking reduction or cessation.