MONOAMINE TRANSPORTERS & NONHUMAN PRIMATE COCAINE

单胺转运蛋白

• 批准号: 7958145
• 负责人: HEATHER L KIMMEL
• 金额: $ 5.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958145
• 关键词: Behavior; Behavioral; Brain; Cocaine; Cocaine Dependence; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Dopamine; Drug Kinetics; Effectiveness; Funding; Grant; Institution; Macaca mulatta; Microdialysis; Neurotransmitters; Norepinephrine; Pharmaceutical Preparations; Pharmacotherapy; Positron-Emission Tomography; Primates; Procedures; Property; Radiolabeled; Relative (related person); Reporting; Research; Research Personnel; Resources; Role; Saimiri; Self-Administered; Serotonin; Source; Stimulus; Time; Training; United States National Institutes of Health; dopamine transporter; in vivo; inhibitor/antagonist; monoamine; neurochemistry; nonhuman primate; radiotracer; reuptake; trend; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Currently, there is no effective medication for treating cocaine addiction. A better understanding of how cocaine exerts its effects on the brain will focus medication development efforts. Although cocaine blocks the reuptake of the monoamine neurotransmitters dopamine, serotonin and norepinephrine, the reinforcing effects of cocaine have been attributed primarily to its effects at the dopamine transporter (DAT). However, not all DAT inhibitors are equally reinforcing. It is important to examine the properties involved in the effects of these compounds. During the reporting period, research has been conducted reinforcing effectiveness of several monoamine transporter inhibitors (DAT-selective and mixed-action) is assessed in nonhuman primates. The stimulant effects of these compounds are assessed by administering them systemically to squirrel monkeys trained on a stimulus-termination task. The reinforcing effects are assessed in separate groups of squirrel monkeys trained to self-administer cocaine. These data will enable us to determine the relative stimulant and reinforcing efficacy and potency of each combination. To determine drug effects on brain dopamine function, squirrel monkeys undergo in vivo microdialysis procedures following drug administration. PET imaging of the uptake of radiolabeled monoamine transporter inhibitors is conducted in rhesus monkeys to correlate drug levels in brain with observed behavior and neurochemistry. The present data showed that the time to peak drug levels in brain were very highly correlated with the time to peak increases in brain dopamine. In addition, the data showed a trend for compounds with a shorter duration of action or DAT selectivity to produce significant behavioral-stimulant and reinforcing effects. These data further characterize the role of pharmacokinetics in the addictive properties of cocaine and provide critical information for the development of effective pharmacotherapies that are not, themselves, addictive.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 目前，没有有效的药物可以治疗可卡因成瘾。更好地了解可卡因如何对大脑发挥作用将集中药物开发工作。尽管可卡因会阻止单胺神经递质多巴胺、血清素和去甲肾上腺素的再摄取，但可卡因的增强作用主要归因于其对多巴胺转运蛋白 (DAT) 的作用。然而，并非所有 DAT 抑制剂都具有同样的增强作用。检查这些化合物的作用所涉及的特性非常重要。 在报告期内，开展了研究，以加强在非人类灵长类动物中评估几种单胺转运蛋白抑制剂（DAT 选择性和混合作用）的有效性。这些化合物的刺激作用是通过将它们全身给予接受刺激终止任务训练的松鼠猴来评估的。在经过自我注射可卡因训练的松鼠猴的不同组中评估了强化效果。这些数据将使我们能够确定每种组合的相对兴奋和增强功效和效力。为了确定药物对大脑多巴胺功能的影响，松鼠猴在给药后进行体内微透析程序。在恒河猴中进行放射性标记单胺转运蛋白抑制剂的摄取的 PET 成像，将大脑中的药物水平与观察到的行为和神经化学联系起来。 目前的数据表明，大脑中药物水平达到峰值的时间与大脑多巴胺增加达到峰值的时间高度相关。 此外，数据显示，具有较短作用持续时间或 DAT 选择性的化合物具有产生显着行为刺激和强化作用的趋势。 这些数据进一步描述了药代动力学在可卡因成瘾特性中的作用，并为开发本身不成瘾的有效药物疗法提供了关键信息。