Intravenous Cocaine Discrimination in Humans

描述（由申请人提供）：可卡因滥用/依赖仍然是一个主要的社会和公共卫生问题。有相当数量的可卡因依赖者，目前的行为治疗干预措施对他们无效。寻找一种成功的可卡因滥用/依赖药物治疗仍然是一个重要但难以实现的目标。在临床前研究中，有几种化合物被证明可以减弱静脉注射可卡因的辨别刺激和强化作用，但当这些药物在临床试验中进行测试时，没有一种被证明是有效的。目前尚不清楚缺乏一致性是否是这些模型中使用的行为程序的功能，还是物种差异。回答这个问题的一个策略是在人类中进行类似的研究，以评估动物模型的有效性。虽然已经建立了研究静脉注射可卡因在人体中的主观、生理和强化作用的方法，但尚未开发出静脉注射可卡因的药物鉴别方法。研究药物的区别性刺激效应的潜在优势在于，这种方法特别适合于研究药物依赖性相关效应的机制，并且具有相对有效的潜力，可以在相对较短的时间内对几种候选药物进行评估。本申请的目的是建立静脉注射可卡因的歧视范例在人类中的有效性。在第一项研究中，人类参与者将接受培训，以区分静脉注射可卡因的影响。然后将用高于和低于训练剂量的可卡因剂量生成剂量-反应函数，并将用与可卡因类似的药物（d-安非他明）和与可卡因不同的药物（戊巴比妥）的剂量进行泛化测试，以确定范例的特异性。第二项研究将确定口服可卡因是否能减弱静脉注射可卡因的主观、生理和辨别刺激效应。虽然口服可卡因不太可能是治疗可卡因依赖的药物，但对可卡因强化作用的研究表明，口服可卡因后，可卡因的强化作用被阻断，在没有既定阻断剂的情况下，这种方法可作为概念验证。这些研究作为一个整体，将调查一个有前途的新战略，开发治疗药物的可卡因滥用/依赖。如果成功的话，这将是一个有效的范例，用于检查化合物的能力，以减轻可卡因在人类的影响，并可能导致一个成功的药物治疗可卡因滥用/依赖。

DESCRIPTION (provided by applicant): Cocaine abuse/dependence remains a major social and public health problem. There are a significant number of cocaine dependent individuals for whom current behavioral treatment interventions are ineffective. Finding a successful pharmacological treatment for cocaine abuse/dependence continues to be an important yet elusive goal. Several compounds have been shown in pre-clinical studies to attenuate the discriminative stimulus and reinforcing effects of intravenous cocaine but when these medications have been tested in clinical trials, none have proven effective. It is not clear whether the lack of concordance is a function of the behavioral procedures that are used in these models or to a species difference. One strategy to answer this question is to conduct similar studies in humans to assess the validity of the animal models. Although there are established methods for studying the subjective, physiological, and reinforcing effects of intravenous cocaine in humans, drug discrimination methods with intravenous cocaine have not been developed. The potential advantage of studying the discriminative stimulus effects of drugs is that this procedure is particularly well suited for studying mechanisms underlying the dependence-related effects of drugs and has the potential to be relatively efficient, allowing several candidate medications to be evaluated over a relatively short period of time. The goal of this application is to establish the validity of an intravenous cocaine discrimination paradigm in humans. In the first study, human participants will be trained to discriminate the effects of intravenous cocaine injections. Dose-response functions will then be generated with cocaine doses higher and lower than the training dose and generalization tests will be conducted with doses of a drug similar pharmacologically to cocaine (d-amphetamine) and a drug different from cocaine (pentobarbital) to determine the specificity of the paradigm. The second study will determine whether oral cocaine can attenuate the subjective, physiological, and discriminative stimulus effects of intravenous cocaine injections. Although oral cocaine would be an unlikely medication for cocaine dependence, studies of the reinforcing effects of cocaine have demonstrated that they are blocked following the administration of oral cocaine and that this approach functions as a proof of concept in the absence of established blocking agents. These studies as a whole will investigate a promising new strategy for developing treatment medications for cocaine abuse/dependence. If successful, this will be an efficient paradigm for examining the ability of compounds to attenuate the effects of cocaine in humans and may lead to a successful pharmacological treatment for cocaine abuse/dependence.