Intravenous Cocaine Discrimination in Humans

说明（由申请人提供）：可卡因滥用/依赖仍然是一个重大的社会和公共卫生问题。有相当数量的可卡因依赖个体，目前的行为治疗干预措施是无效的。找到一种成功的药物治疗可卡因滥用/依赖仍然是一个重要但难以实现的目标。临床前研究表明，有几种化合物可以减弱静脉注射可卡因的区别性刺激和强化作用，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身上进行类似的研究，以评估动物模型的有效性。虽然有既定的方法来研究人类静脉注射可卡因的主观、生理和强化效应，但静脉注射可卡因的药物鉴别方法尚未发展起来。研究药物的区别性刺激效应的潜在优势在于，这种方法特别适合研究药物依赖相关效应的潜在机制，并且具有相对有效的潜力，允许在相对较短的时间内评估几种候选药物。这个应用程序的目标是建立在人类静脉注射可卡因歧视范式的有效性。在第一项研究中，人类参与者将接受训练，辨别静脉注射可卡因的效果。然后，在可卡因剂量高于和低于训练剂量的情况下产生剂量-反应函数，并用药理学上与可卡因相似的药物（d-安非他明）和与可卡因不同的药物（戊巴比妥）的剂量进行泛化试验，以确定范式的特异性。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、生理和鉴别刺激效应。虽然口服可卡因不太可能是治疗可卡因依赖的药物，但对可卡因强化效应的研究表明，在口服可卡因后，它们会被阻断，这种方法在缺乏既定阻断剂的情况下，可以作为概念的证明。这些研究作为一个整体将探讨一种有希望的新策略，用于开发治疗可卡因滥用/依赖的药物。如果成功，这将是一个有效的范例，用于检查化合物减轻可卡因对人体的影响的能力，并可能导致对可卡因滥用/依赖的成功药理学治疗。

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.