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。这项申请建立在这样一个命题上，即可卡因药物疗法开发的转化研究将受益于在动物和人类中使用协调和同源程序来研究候选药物对可卡因和非药物增强剂之间选择的影响。该项目将使用自我管理程序，因为药物的强化作用是药物滥用和成瘾的核心。将提供可卡因的替代增强剂，因为选择使用可卡因而排除其他行为是依赖的标志，有效的药物应该帮助患者减少药物使用，并将行为从药物使用重新分配到更负责任和更有成效的活动。将临床前研究纳入药物开发过程的优势包括对环境和受试者病史的严格控制，以及测试新化合物和/或在人体上不可行的广泛剂量范围。恒河猴之所以被选为动物对象，是因为它们在系统发育上与人类的亲缘关系比啮齿动物更近，而且可以通过长期留置静脉导管进行器械治疗，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人群中测试滥用药物对挑战的假定药物治疗效果。将恒河猴和人类实验室模型配对的另一个好处是，强大的受试者内设计可以用于这两个物种。尽管人类和非人类灵长类动物的方法具有相对的优势，但由于使用了截然不同的自我给药程序和药物治疗方案，翻译研究一直受到阻碍。拟议的项目旨在协调恒河猴和人类用于筛选药物的程序，首先建立平行的自我给药方法，将使用相同的可卡因剂量、可卡因给药途径和加强时间表，以及有效减少吸毒的特定物种替代增强剂。然后将调整可卡因剂量、时间表参数和替代增强剂的大小，以在d-苯丙胺维持试验之前获得同等的功能效果。D-苯丙胺的使用将允许平衡跨物种的敏感性，并为未来研究中检查的其他非多巴胺能候选药物的效果提供一个比较器。通过建立一个将动物和人类方法紧密联系在一起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。拟议的项目具有很高的创新性，它将在非人类灵长类动物和人类身上开发协调和相应的程序，使用复杂的可卡因选择程序，旨在开发治疗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.