MONOAMINE TRANSPORTERS & NONHUMAN PRIMATE COCAINE

单胺转运蛋白

• 批准号: 7715714
• 负责人: HEATHER L KIMMEL
• 金额: $ 3.56万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715714
• 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; Procedures; Property; Radiolabeled; Relative (related person); 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. In the present research, the 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 目前，没有有效治疗可卡因成瘾的药物。更好地了解可卡因如何对大脑发挥作用将集中用药开发工作。尽管可卡因阻止了单胺神经递质多巴胺，5-羟色胺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在多巴胺转运蛋白（DAT）上的作用。但是，并非所有DAT抑制剂都同样加强。重要的是检查这些化合物的作用所涉及的特性。在本研究中，在非人类灵长类动物中评估了几种单胺转运蛋白抑制剂（Dat-Selece和混合作用）的增强有效性。这些化合物的刺激作用是通过系统地对受刺激终止任务训练的松鼠猴进行系统施用来评估的。在接受自助剂可卡因训练的小鼠猴子中评估了增强作用。这些数据将使我们能够确定每种组合的相对刺激性和增强功效和效力。为了确定药物对脑多巴胺功能的影响，松鼠猴在药物给药后接受了体内微透析手术。放射性标记的单胺转运蛋白抑制剂的宠物成像是在恒河猴中进行的，以将大脑中的药物水平与观察到的行为和神经化学相关联。目前的数据表明，大脑中峰值药物水平的时间与脑多巴胺峰增加的时间非常相关。 此外，数据显示了具有较短的作用持续时间或DAT选择性的化合物的趋势，以产生重要的行为刺激和增强作用。 这些数据进一步表征了药代动力学在可卡因成瘾性特性中的作用，并为开发没有上瘾的有效药物疗法提供关键信息。