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。本申请的基础是，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，以研究候选药物对可卡因和非药物替代品之间选择的影响。本项目将采用自我给药程序，因为药物的强化作用是药物滥用和产生依赖性的关键。将提供可卡因的替代药物，因为选择使用可卡因而排除其他行为是依赖的标志，有效的药物应有助于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。在药物开发过程中纳入临床前研究的优势包括严格控制环境和受试者病史，以及测试在人类中不可行的新型化合物和/或广泛的剂量范围。选择恒河猴作为动物受试者，因为它们在遗传学上与人类的关系比啮齿动物更密切，并且可以使用长期留置IV导管，这有助于实施药物与食物选择程序。人体实验室研究允许在临床相关受试者人群中检测滥用药物激发的推定药物治疗作用。配对恒河猴和人类实验室模型的另一个优点是，强大的受试者内设计可以用于两个物种。尽管人类和非人类灵长类动物的方法相对较强，但转化研究受到了使用广泛不同的自我管理程序和药物治疗方案的阻碍。拟议的项目力求统一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，使用相同的可卡因剂量、可卡因给药途径和强化时间表，以及有效减少吸毒的特定物种替代药物。然后将调整可卡因剂量、时间表参数和替代性兴奋剂幅度，以在d-苯丙胺维持试验之前获得等效的功能效应。使用d-苯丙胺将允许平衡跨物种敏感性，并为未来研究中检查的其他非多巴胺能候选药物的作用提供比较。实现该项目的目标将通过建立一个可卡因药物筛选研究平台产生持续和强大的影响，该平台将密切联系动物和人类方法，从而加速药物开发的转化研究。拟议的项目具有高度创新性，因为它将使用先进的可卡因选择程序，在非人类灵长类动物和人类中开发协调一致的程序，目的是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.