Evaluation of Novel Treatments for Stimulant Dependence

描述（由申请人提供）：美国最近的调查显示，在过去的一个月里，大约有260万人报告使用可卡因/快克。尽管有协调一致的研究努力来开发有效的药物治疗，但尚未发现广泛有效的治疗方法。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失调。本申请建议通过在人类实验室环境中采用控制良好的实验方法，检查一种新型药物阿立哌唑（Abilify）对可卡因的潜在功效。阿立哌唑是美国最新上市的非典型抗精神病药物；它的神经药理学特征是真正独特的，并将其与所有其他非典型抗精神病药区分开来。阿立哌唑对D2和5-HT1a受体具有高亲和力，可作为部分激动剂，对5-HT2受体具有高亲和力，可作为拮抗剂。我们假设阿立哌唑可能阻断可卡因的突触效应，并改善长期使用可卡因造成的神经紊乱。健康的成人可卡因依赖志愿者（n=36）也吸烟，将被登记为住院患者，为期45天。在短暂的洗脱期和单盲安慰剂引入后，他们将在双盲条件下被随机分配到3个治疗组中的一个（0、15或30毫克阿立哌唑每日1次）。可卡因挑战环节将在安慰剂引入、急性给药阶段和稳定状态下进行。在每个阶段，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将在可卡因剂量效应挑战环节中进行检查。阿立哌唑治疗对可卡因强化效应的影响将直接通过采用替代强化剂的自我给药程序进行检查，并已由我们的实验室进行了很好的表征。将对与非法使用可卡因有关的一系列剂量进行检查，药效学评估将是多方面的，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减少吸烟，第二个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来检查在禁闭期间受控条件下的吸烟情况；将采用吸烟地形程序和自然吸烟措施。总体而言，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，同时提供开展门诊临床试验所需的必要安全性数据，并探索该药物减少或戒烟的潜在功效。

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.