EVALUATION OF NOVEL TREATMENTS FOR STIMULANT DEPENDENCE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 可卡因滥用继续在美国造成重大的公共卫生问题，没有广泛有效的治疗方法。 可卡因具有广泛的药理学作用，但几十年的多学科研究已经形成了公认的理论，即中边缘-皮质多巴胺系统在介导可卡因滥用相关的强化作用方面起着关键作用。 此外，记录的多巴胺系统的神经扰动是由长期使用可卡因引起的，并被假设为戒断期间发生的持续渴望和戒断症状的基础。 然而，评价多巴胺药物的临床研究未能证明对可卡因使用的疗效;这些结果部分归因于与临床可用的多巴胺激动剂和传统多巴胺拮抗剂相关的不良反应。 最近，理论上认为，在多巴胺受体位点具有部分激动剂/拮抗剂性质的化合物可以提供有效的药理学策略，降低不可耐受的副作用的风险。 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将其与所有其他非典型抗精神病药区分开来。 与其他非典型抗精神病药的拮抗剂作用相反，阿立哌唑对D2受体表现出高亲和力，表现为部分激动剂。 阿立哌唑也可作为5-HT 1a的部分激动剂和5-HT 2受体的拮抗剂。 这些受体系统被认为在情绪调节中起着重要作用，并且这些位点的活性已被证明可以在各种范例中改变可卡因的作用。结合受体的作用加上其中间的内在疗效，导致阿立哌唑作为一类新的药物，多巴胺-5-羟色胺稳定剂的特点。 我们假设阿立哌唑可能通过直接阻断其急性效应和恢复慢性可卡因使用失调的系统的神经稳态来有效对抗可卡因使用。 阿立哌唑也可能对吸烟有治疗效果。 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，与维持传统抗精神病药物治疗的患者的基线吸烟率相比，非典型抗精神病药物可显著减少吸烟。 总之，这些有趣的数据表明，非典型抗精神病药物，其结合多巴胺和血清素的活动，可能是一个有用的策略，以减少吸烟。 目前的住院研究，其主要目的是评估阿立哌唑对可卡因的疗效，提供了一个独特的机会，探索吸烟的影响作为次要目的。 该项目的主要目的是：1）评价阿立哌唑在可卡因和烟草依赖者中的安全性和耐受性， 2)评价与安慰剂相比阿立哌唑减弱可卡因的与其滥用倾向相关的积极主观效应的能力，和3）通过采用可卡因自我给药的经验证的实验室程序直接评价阿立哌唑降低可卡因的强化功效的功效。 本项目的次要目的是：1）使用吸烟地形图的对照实验室方法评价阿立哌唑在一定剂量范围内减少吸烟的疗效，2）在对照住院实验室环境中评价阿立哌唑对随意吸烟的影响。 该项目将招募健康的、依赖可卡因的吸烟者志愿者。 在研究期间，他们将作为住院患者在仔细的药物监督下住院。 该研究将采用双盲、随机、平行组、多剂量设计，以探索阿立哌唑对可卡因和吸烟结局的影响。 计划使用的方法已经在我们的实验室开发并成功应用。 我们假设与安慰剂相比，阿立哌唑治疗将显著降低对可卡因的阳性主观反应，并显著降低可卡因自我给药。 我们还假设，与安慰剂相比，阿立哌唑治疗会显著减少吸烟行为。 该项目将提供关于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，同时产生启动门诊临床试验所需的必要安全性相互作用数据，以评估阿立哌唑在门诊可卡因依赖个体中的作用。

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.