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）的此PET成像部分的主要目标是通过评估与健康对照对象（HC）相比，通过评估可卡因依赖性（CD）受试者的神经化学和行为差异，以评估与药物滥用相关的两种主要类型的脉冲行为（冲动性选择和冲动反应）相关的神经机制。我们建议比较[11C] Phn0（一种有效的多巴胺D2/D3 PET pET激动剂配体）在HC和CD的腹侧和背侧纹状体中（具体目标1），然后将结合潜力与在任务中进行选择的响应（Project 1）与事件相关的BOLD活动相关联（在任务中评估）和任务的响应（Project 1）。我们进一步提议在大鼠和非人类中进行宠物成像 可卡因暴露前后的灵长类动物使用相同的认知/行为任务将多巴胺D2/D3的可用性与冲动性措施相关联。这是第一项专门设计的研究，旨在表征所有三个物种的冲动性，无论是行为和神经化学上的，并研究了冲动与可卡因成瘾的关系。拟议的翻译研究将提供 通过将临床和临床前的发现联系起来，以解决影响成瘾责任的因素或对药物影响的脆弱性，可能导致滥用和补充的神经生物学改变以及滥用药物如何影响脑系统和过程的脑系统变化后，暴露于药物后会随时间变化的脑系统和过程如何，协同信息的信息是解决了临床和临床前的发现。通过采用神经影像技术（项目2）与索菲的功能和行为测量范式配对（项目 1＆3），通过整合病毒介导的基因表达研究（项目4），我们可以更好地理解可卡因在Mulfiple水平上诱导的替代品，包括分子基因FEC，神经和行为水平。因此，拟议的研究具有显着的能力，可以产生结果，可以为可卡因成瘾的人类成瘾提供依据。