Monoamine Transporters and Nonhman Primate Cocaine Use

单胺转运蛋白和非人类灵长类可卡因使用

• 批准号: 7090080
• 负责人: HEATHER L KIMMEL
• 金额: $ 13.86万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7090080
• 关键词: Macaca mulatta; Rodentias; Saimiri; behavior test; behavioral /social science research tag; cocaine; dopamine transporter; dosage; drug abuse; methylphenidate; microdialysis; neurochemistry; neurotransmitter antagonist; neurotransmitter transport; pharmacokinetics; positron emission tomography; postdoctoral investigator; psychological reinforcement; psychopharmacology; self medication; stereotaxic techniques; stimulant /agonist

DESCRIPTION (provided by applicant): To date, there is no effective medication for treating cocaine addiction. A better understanding of the manner by which 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 primarily attributed to its effects at the dopamine transporter (DAT). However, not all DAT inhibitors are equally reinforcing. Examining the pharmacokinetics, more specifically, the onset and duration of action, of cocaine and related compounds is important in determining which of these properties are involved in the reinforcing effects of these compounds. In the present research proposal, the reinforcing effectiveness of several monoamine transporter inhibitors (DAT-selective and mixed-action) will be assessed in nonhuman primates. The stimulant effects of these compounds will be assessed by administering them systemically to squirrel monkeys trained on a stimulus termination task. The reinforcing effects will be assessed in separate groups of squirrel monkeys and rhesus monkeys that have been trained to self-administer cocaine. These data will allow us to determine the relative stimulant and reinforcing efficacy and potency of each combination. To determine drug effects on brain dopamine function, squirrel monkeys will undergo in vivo microdialysis procedures following drug administration, allowing us to determine how dopamine levels are altered by the administration of these drug combinations. PET imaging of DAT occupancy will be conducted in rhesus monkeys, allowing us to correlate DAT occupancy with the observed behavior and neurochemistry. Ex vivo binding assays will be conducted in rodents to determine the rate that these compounds bind to DAT. These data will 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. This research proposal will extend the candidate's research training in rodent behavioral pharmacology and neurochemistry to nonhuman primate behavioral pharmacology and neurochemistry. In addition, this research plan represents a new research direction for the applicant. The training experiences described will provide for the candidate's transition from a mentored scientist to an independent investigator.

描述（由申请人提供）： 迄今为止，还没有有效的药物可以治疗可卡因成瘾。更好地了解可卡因对大脑产生影响的方式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。检查可卡因和相关化合物的药代动力学，更具体地说，作用的起效和持续时间对于确定这些特性中的哪些与这些化合物的增强作用有关非常重要。在本研究计划中，将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）的增强效果。这些化合物的刺激作用将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。强化效果将在经过自我注射可卡因训练的松鼠猴和恒河猴的不同组中进行评估。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，松鼠猴将在给药后进行体内微透析程序，从而使我们能够确定这些药物组合的给药如何改变多巴胺水平。 DAT 占据的 PET 成像将在恒河猴中进行，使我们能够将 DAT 占据与观察到的行为和神经化学联系起来。将在啮齿类动物中进行离体结合测定，以确定这些化合物与 DAT 结合的速率。这些数据将进一步表征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关键信息。该研究计划将把候选人在啮齿动物行为药理学和神经化学方面的研究培训扩展到非人类灵长类动物行为药理学和神经化学。此外，该研究计划代表了申请人的一个新的研究方向。所描述的培训经历将使候选人从受指导的科学家转变为独立研究者。