Medications Development for Cocaine: A Translational Approach in Monkey and Human

描述（由申请人提供）：可卡因使用障碍仍然是一个重大的公共卫生问题，但尚未确定有效的药物治疗方法。这项申请是基于这样一个命题：在动物和人类中使用协调和同源的程序来研究候选药物对可卡因和非药物强化剂之间选择的影响，将有利于可卡因药物治疗发展的转化研究。本项目将采用自我给药程序，因为药物的强化作用是其滥用和发展依赖的核心。将提供可卡因的替代强化物，因为选择使用可卡因而排除其他行为是依赖的标志，有效的药物应帮助患者减少吸毒，并将吸毒行为重新分配到更负责任和更有成效的活动中。在药物开发过程中纳入临床前研究的优点包括严格控制环境和受试者历史，以及测试新化合物和/或大剂量范围，这些在人类中是不可行的。之所以选择恒河猴作为实验对象，是因为恒河猴在系统发育上与人类的关系比啮齿类动物更密切，而且恒河猴可以长期留置静脉导管，这有助于实施药物与食物的选择程序。人体实验室研究允许在临床相关的受试者群体中测试滥用药物对假定药物治疗的影响。将恒河猴和人类实验室模型配对的另一个好处是，强大的受试者内部设计可以用于两个物种。尽管人类和非人类灵长类动物方法具有相对优势，但由于使用了广泛不同的自我给药程序和药物治疗方案，转化研究受到了阻碍。拟议的项目旨在通过首先建立平行的自我给药方法来协调恒河猴和人类用于筛选药物的程序，这些方法将使用相同的可卡因剂量，可卡因给药途径和强化时间表，以及有效减少药物服用的物种特异性替代强化剂。然后，在d-安非他明维持试验之前，将调整可卡因剂量、时间表参数和替代强化剂的大小，以获得等效的功能效果。d-安非他明的使用将允许平衡跨物种敏感性，并为其他非多巴胺能候选药物的影响提供比较物，在未来的研究中进行检查。通过建立一个将动物和人类方法紧密联系起来的可卡因药物筛选研究平台，从而加速药物开发的转化研究，实现该项目的目标将产生持续和强大的影响。拟议的项目是高度创新的，因为它将在非人类灵长类动物和人类中开发协调和同源的程序，使用复杂的可卡因选择程序，旨在开发用于可卡因使用障碍的药物。

DESCRIPTION (provided by applicant): Cocaine-use disorders continue to be a significant public health concern, yet no effective pharmacological treatments have been identified. This application is founded on the proposition that translational research on development of cocaine pharmacotherapies will benefit from the use of coordinated and homologous procedures in animals and humans to study effects of Candidate medications on choice between cocaine and a non-drug reinforcer. Self-administration procedures will be used in this project because the reinforcing effects of drugs are central to their abuse and the development of dependence. An alternative reinforcer to cocaine will be offered because the choice to use cocaine to the exclusion of other behaviors is a hallmark of dependence, and an effective medication should assist patients in reducing drug use and reallocating behavior from drug use to more responsible and productive activities. Advantages of including preclinical research in the medications development process include strict control over environment and subject history, and testing novel compounds and/or extensive dose ranges not feasible in humans. Rhesus monkeys were selected as the animal subjects because they are phylogenetically more closely related to humans than rodents, and can be instrumented with chronically indwelling IV catheters, which facilitates implementation of drug vs. food choice procedures. Human laboratory research permits the testing of putative pharmacotherapy effects on challenges with the abused drug in a clinically relevant subject population. Another advantage of pairing rhesus monkey and human laboratory models is that powerful within-subjects designs can be used with both species. Despite the relative strengths of human and non-human primate approaches, translational research has been hampered by the use of widely different self-administration procedures and medication treatment regimens. The proposed project seeks to harmonize rhesus monkey and human procedures used to screen medications by first establishing parallel self-administration methods that will employ the same cocaine doses, route of cocaine administration and schedule of reinforcement, as well as a species-specific alternative reinforcer that effectively reduces drug taking. Cocaine doses, schedule parameters and alternative reinforcer magnitude will then be adjusted to obtain equivalent functional effects prior to d-amphetamine maintenance testing. The use of d-amphetamine will permit equilibration of cross-species sensitivity and provide a comparator for effects of other, non-dopaminergic Candidate medications examined in future studies. Achieving the aims of this project will exert a sustained and powerful impact by establishing a research platform for cocaine medication screening that will tightly link animal and human approaches thereby accelerating translational research on medications development. The proposed project is highly innovative in that it will develop coordinated and homologous procedures in nonhuman primates and humans using sophisticated cocaine choice procedures aimed towards medications development for cocaine-use disorders.