EVALUATION OF NOVEL TREATMENTS FOR STIMULANT DEPENDENCE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在美国，可卡因滥用仍然是一个严重的公共卫生问题，目前还没有广泛有效的治疗方法。可卡因具有广泛的药理作用，但几十年的多学科研究已经形成了公认的理论，即中脑边缘-皮质多巴胺系统在调节与滥用可卡因有关的强化效应方面发挥着关键作用。此外，记录在案的多巴胺系统神经紊乱是由长期使用可卡因引起的，并被假设为在戒断期间发生持续渴望和戒断症状的基础。然而，评估多巴胺药物的临床研究未能证明对抗可卡因使用的有效性；这些结果在一定程度上可归因于临床上可用的多巴胺激动剂和传统的多巴胺拮抗剂的不良反应。最近，有理论认为，在多巴胺受体位置具有部分激动剂/拮抗剂特性的化合物可能提供一种有效的药理策略，同时降低无法耐受的副作用的风险。 阿立哌唑是在美国上市的最新非典型抗精神病药物。它的神经药理学特征使其有别于所有其他非典型抗精神病药物。与其他非典型抗精神病药物的拮抗作用不同，阿立哌唑对D2受体表现出高亲和力，表现为部分激动剂。阿立哌唑还作为5-HT1a的部分激动剂和5-HT2受体的拮抗剂。这些受体系统被认为在情绪调节中发挥着重要作用，这些部位的活动已被证明在各种范式中改变了可卡因的影响。阿立哌唑是一种新型的多巴胺-5-羟色胺稳定剂，其受体的联合作用加上其中间的内在效应使得阿立哌唑成为一种新的药物。我们推测，阿立哌唑可能通过直接阻断其急性效应和恢复因长期使用可卡因而失调的系统的神经稳态来有效地对抗可卡因的使用。 阿立哌唑也可能对吸烟有治疗作用。临床研究表明，D2受体活性可以改变正常吸烟者的吸烟行为。此外，对吸烟的精神分裂症患者的研究表明，当患者继续使用传统抗精神病药物时，与基线相比，非典型抗精神病药物可能显著减少吸烟。总而言之，这些耐人寻味的数据表明，非典型抗精神病药物，加上它们的多巴胺和5-羟色胺活性，可能是减少吸烟的有用策略。目前的住院研究的主要目的是评估阿立哌唑对可卡因的疗效，它提供了一个独特的机会来探索吸烟的影响作为次要目标。 该项目的主要目的是：1)评估阿立哌唑在可卡因和烟草依赖者身上的安全性和耐受性， 2)与安慰剂相比，评价阿立哌唑减弱与其滥用倾向相关的积极主观效应的能力；3)采用经过验证的可卡因自我给药的实验室程序，直接评价阿立哌唑降低可卡因强化效应的有效性。该项目的次要目标是：1)使用吸烟地形学的受控实验室方法学评估一定剂量范围内的阿立哌唑减少吸烟的效果，以及2)在受控的住院患者实验室环境中评估阿立哌唑对即兴吸烟的影响。 该项目将招募吸烟者、健康、依赖可卡因的志愿者。在研究期间，他们将作为住院患者在仔细的药物监督下居住。这项研究将采用双盲、随机、平行分组、多剂量设计来探索阿立哌唑对可卡因和吸烟结果的影响。计划使用的方法已经开发出来，并在我们实验室成功应用。我们假设，与安慰剂相比，阿立哌唑治疗将显著减少对可卡因的积极主观反应，并将显著减少可卡因的自我给药。我们还假设，与安慰剂相比，阿立哌唑治疗后吸烟行为将显著减少。该项目将提供有关阿立哌唑治疗可卡因依赖和烟草依赖的相对安全性和有效性的重要新信息，同时提供开展门诊临床试验所需的必要的安全交互数据，以评估门诊可卡因依赖者的阿立哌唑。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cocaine abuse continues to pose a significant public health problem in the U.S. with no broadly effective treatment available. Cocaine exerts a broad array of pharmacological effects, but several decades of multidisciplinary research have led to the accepted theory that the mesolimbic-cortical dopamine system plays a critical role in mediating the reinforcing effects of cocaine related to its abuse. Moreover, documented neural perturbations in dopamine systems result from chronic cocaine use and are hypothesized to underlie the persistent craving and withdrawal symptoms that occur during abstinence. Clinical studies evaluating dopamine agents have, however, failed to demonstrate efficacy against cocaine use; these results are attributable, in part, to the adverse effects associated with the clinically available dopamine agonists and traditional dopamine antagonists. More recently, it has been theorized that compounds with partial agonist/antagonist properties at dopamine receptor sites may provide an effective pharmacological strategy with a decreased risk of intolerable side effects. Aripiprazole is the newest atypical antipsychotic marketed in the United States. Its neuropharmacological profile distinguishes it from all other atypical antipsychotics. Aripiprazole exhibits high affinity for the D2 receptor where it behaves as a partial agonist, in contrast to the antagonist actions of other atypical antipsychotics. Aripiprazole also acts as a partial agonist at the 5-HT1a and as an antagonist at 5-HT2 receptors. These receptor systems are recognized as playing an important role in mood regulation, and activity at these sites has been shown to modify the effects of cocaine in a variety of paradigms. The combined receptor actions coupled with its intermediate intrinsic efficacy have led to the characterization of aripiprazole as a new class of agent, a dopamine-serotonin stabilizer. We hypothesize that aripiprazole may be effective against cocaine use by direct blockade of its acute effects and through restoration of neural homeostasis of systems dysregulated by chronic cocaine use. Aripiprazole may also have therapeutic efficacy against cigarette smoking. Clinical studies suggest that D2 receptor activity can modify smoking behavior in normal smokers. Moreover, studies in schizophrenics who smoke suggest that atypical antipsychotic agents may significantly reduce cigarette smoking in comparison to baseline rates when patients are maintained on traditional antipsychotics. Together, these intriguing data suggest that atypical antipsychotic medications, with their combined dopamine and serotonin activities, may be a useful strategy for reducing cigarette smoking. The present inpatient study, whose principal aim is to evaluate the efficacy of aripiprazole against cocaine, provides a unique opportunity to explore the effects on smoking as a secondary aim. The primary aims of this project are to: 1) evaluate the safety and tolerability of aripiprazole over a range of doses in individuals who are cocaine and tobacco dependent, 2) evaluate the ability of aripiprazole to attenuate the positive subjective effects of cocaine related to its abuse liability in comparison to placebo, and 3) evaluate directly the efficacy of aripiprazole to reduce the reinforcing efficacy of cocaine by employing validated laboratory procedures of cocaine self-administration. The secondary aims of this project are to: 1) evaluate the efficacy of aripiprazole over a range of doses to reduce cigarette smoking using controlled laboratory methodology of smoking topography, and 2) evaluate the effect of aripiprazole on ad lib smoking in a controlled inpatient laboratory environment. This project will enroll healthy, cocaine-dependent volunteers who are cigarette smokers. They will reside as inpatients under careful medication supervision for the study duration. The study will employ a double-blind, randomized, parallel group, multi-dose design to explore the effect of aripiprazole on cocaine and cigarette smoking outcomes. The methods planned for use have been developed and successfully employed in our laboratory. We hypothesize that aripiprazole treatment will significantly reduce the positive subjective response to cocaine and will significantly reduce cocaine self-administration in comparison to placebo. We also hypothesize that significant reductions in smoking behavior will occur in response to aripiprazole treatment in comparison to placebo. This project will provide important new information on the relative safety and efficacy of aripiprazole for the treatment of cocaine dependence and tobacco dependence, while producing the requisite safety interaction data needed for the launch of an outpatient clinical trial to evaluate aripiprazole in outpatient cocaine dependent individuals.