Cocaine, Impulsivity, and PHNO Across Species

可卡因、冲动和跨物种的 PHNO

• 批准号: 7797226
• 负责人: YU-SHIN DING
• 金额: $ 15.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797226
• 关键词: Address; Affect; Affinity; Agonist; Animal Behavior; Anterior; Behavior; Behavioral; Binding; Binding Sites; Biological; Brain; Clinical; Cocaine; Cocaine Dependence; Cognitive; Complex; Corpus striatum structure; Data; Dimensions; Dissociation; Dopamine; Dorsal; Drug abuse; Equilibrium; Event; Exposure to; Functional Magnetic Resonance Imaging; Gene Expression; Goals; Health; Human; Image; Impulsive Behavior; Impulsivity; Lead; Ligands; Link; Measures; Mediating; Methods; Modeling; Molecular; Neurobiology; Normal Pressure Hydrocephalus; Pharmaceutical Preparations; Positron-Emission Tomography; Process; Property; Rattus; Research; Rewards; Rodent; Role; Signal Transduction; Substance abuse problem; System; Technology; Testing; Time; Ventral Striatum; Viral; Work; addiction; base; behavior measurement; cingulate cortex; cocaine exposure; design; drug of abuse; interest; neurochemistry; neuroimaging; neuromechanism; nonhuman primate; novel; performance tests; pre-clinical; radioligand; radiotracer; receptor; receptor density; relating to nervous system; response; therapy development

The main goal of this PET imaging section of the P20 proposal (Project 2) is to better understand the neural mechanisms associated with the two major types of impulsive behavior (impulsive choice and impulsive response) as related to drug abuse, by assessing the neurochemical and behavioral differences in cocaine dependent (CD) subjects as compared to healthy control (HC) subjects. We propose to compare the binding potential of [11C]PHN0, a potent dopamine D2/D3 PET agonist ligand, in ventral and dorsal striatum of HC and CD (Specific Aim 1), and then correlate the binding potential with the event-related BOLD activity measured by fMRI (Project 1) during a task assessing impulsive choice and during a task assessing impulsive response (Specific Aim 2). We further propose to conduct PET imaging in rats and non-human primates before and after cocaine exposure and correlate the results on the dopamine D2/D3 availability with impulsivity measures using the same cognitive/behavior tasks. This is the first study specifically designed to characterize impulsivity across all three species, both behaviorally and neurochemically, and to investigate the relationship of impulsivity to cocaine addiction. The proposed translafional research will provide synergisfic informafion by linking the clinical and preclinical findings to address a major gap in our understanding of the factors that influence addiction liability or vulnerability to the effects of drugs, the neurobiological alterations that may lead to abuse and addicfion, and how drugs of abuse may affect brain systems and processes that change over time after exposure to drugs. By employing neuroimaging technology (Project 2) paired with sophisficated functional and behavioral measurement paradigms (Project 1 & 3), and by integrating viral-mediated gene expression study (Project 4), we can begin to better understand the alterafion induced by cocaine at mulfiple levels, including the molecular genefic, neural and behavioral levels. Thus, the proposed study has significant potenfial to yield results that can be inform treatment development for cocaine addiction in humans.

P20提案（项目2）的PET成像部分的主要目标是通过评估可卡因依赖（CD）受试者与健康对照（HC）受试者相比的神经化学和行为差异，更好地了解与药物滥用相关的两种主要类型冲动行为（冲动选择和冲动反应）相关的神经机制。我们建议比较[11 C] PHN 0，一种有效的多巴胺D2/D3 PET激动剂配体，在腹侧和背侧纹状体的HC和CD（具体目标1）的结合电位，然后相关的结合电位与事件相关的BOLD活动的功能磁共振成像（项目1）在评估冲动选择的任务，并在评估冲动反应的任务（具体目标2）。我们进一步建议在大鼠和非人类中进行PET成像。 在可卡因暴露之前和之后的灵长类动物，并使用相同的认知/行为任务将多巴胺D2/D3可用性的结果与冲动性测量相关联。这是第一项专门设计用于表征所有三个物种的冲动性的研究，包括行为学和神经化学，并调查冲动性与可卡因成瘾的关系。拟议的研究将提供 通过将临床和临床前发现联系起来，提供协同信息，以解决我们对影响成瘾倾向或对药物影响的脆弱性的因素、可能导致滥用和成瘾的神经生物学改变以及滥用药物如何影响的理解方面的重大差距。可能影响大脑系统和暴露于药物后随着时间的推移而变化的过程。通过采用神经影像技术（项目2）与复杂的功能和行为测量范式（项目3）， 结合病毒介导的基因表达研究（项目4），我们可以开始从分子遗传、神经和行为等多个水平更好地了解可卡因诱导的变异。因此，拟议的研究具有重要的潜力，可以为人类可卡因成瘾的治疗开发提供信息。