Functional Brain Mapping of Cocaine Action

可卡因作用的大脑功能图谱

• 批准号: 6358941
• 负责人: BARRY E KOSOFSKY
• 金额: $ 16.18万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6358941
• 关键词: bioimaging /biomedical imaging; biological signal transduction; brain imaging /visualization /scanning; brain mapping; brain metabolism; cocaine; deoxyglucose; dopamine; dopamine receptor; dopamine transporter; functional magnetic resonance imaging; gamma aminobutyrate; gene expression; genetically modified animals; laboratory mouse; laboratory rat; microdialysis; neuropharmacology; neurotransmitter metabolism; prosencephalon; serotonin; serotonin receptor; ultrasound blood flow measurement

While the acquisition and use of cocaine continue to have a major impact on public health and safety, advances in the understanding of how cocaine and other drugs of abuse exert their acute and chronic actions on the brain remain elusive. The development of non-invasive functional imaging techniques have provided sensitive and increasingly specific means by which neural processes can be studied with high spatial and temporal resolution. Building upon methods developed and results obtained during the first five years of finding, the experiments proposed in this competing renewal of Project 3 focus on informative rodent models, utilizing chronic cocaine self-administering rats, three lines of knockout mice, as well as drug-naive controls. We propose experiments using functional MRI (fMRI), laser doppler flowmetry, 2-DG metabolic mapping, and in vivo microdialysis methods to study mechanisms of cocaine action. Specific Aim 1 investigates the linkage between dopaminergic activity in brain reward circuits and generation of fMRI signals, and explores the role of serotonergic and GABAergic systems in modulating that activity. Specific Aim 2 utilizes fMRI in mice in which the gene coding for the dopamine transporter, or the D1a receptor, or th4e 5-HT1b receptor has been rendered inoperative. We anticipate that results from these experiments will provide confirmatory evidence to the pharmacological experiments proposed in Specific Aim 1, identifying the role of particular molecular components of dopaminergic and serotonergic signal transduction that contribute to cocaine-induced brain activation. Building upon results from Specific Aim 1, Specific Aim 3 investigates the role of dopaminergic and serotonergic systems in long-term adaptations which occur as a consequence of chronic cocaine exposure using a cocaine self- administration paradigm, the closest animal model of human substance abuse currently available. The hypothesis-driven experiments using state of the art functional imaging techniques that we have proposed in Project 1, in concert with experiments proposed in Project 2, focused on identifying mechanisms coupling psychostimulant administration to cerebral vascular response, are designed to provide a deeper understanding of the mechanism of cocaine action. These experiments in rodents will advance our understanding of acute and chronic effects of cocaine on brain function, facilitating interpretation of data from Project 1, thereby providing a crucial link in understanding the fMRI correlates and neurobiologic consequences of cocaine addiction in humans.

虽然可卡因的获取和使用继续对公共健康和安全产生重大影响，但对可卡因和其他滥用药物如何对大脑产生急性和慢性作用的理解仍然难以捉摸。非侵入性功能成像技术的发展提供了灵敏且日益具体的手段，通过这些手段可以以高空间和时间分辨率研究神经过程。基于前五年发现的方法和获得的结果，项目 3 的竞争性更新中提出的实验侧重于信息丰富的啮齿动物模型，利用慢性可卡因自我给药大鼠、三系基因敲除小鼠以及未接受药物的对照。我们建议使用功能性 MRI (fMRI)、激光多普勒血流测定法、2-DG 代谢图谱和体内微透析方法进行实验来研究可卡因作用机制。具体目标 1 研究大脑奖赏回路中的多巴胺能活动与 fMRI 信号生成之间的联系，并探讨血清素能和 GABA 能系统在调节该活动中的作用。具体目标 2 在小鼠中利用功能磁共振成像，其中编码多巴胺转运蛋白、D1a 受体或 th4e 5-HT1b 受体的基因已失效。我们预计这些实验的结果将为具体目标 1 中提出的药理学实验提供确凿的证据，确定多巴胺能和血清素能信号转导的特定分子成分对可卡因诱导的大脑激活的作用。基于特定目标 1 的结果，特定目标 3 使用可卡因自我给药范式（目前可用的最接近的人类药物滥用动物模型）研究了多巴胺能和血清素能系统在长期适应中的作用，这种长期适应是由于长期接触可卡因而发生的。我们在项目 1 中提出的假设驱动实验使用最先进的功能成像技术，与项目 2 中提出的实验相结合，重点是确定精神兴奋剂给药与脑血管反应的耦合机制，旨在提供对可卡因作用机制的更深入的理解。这些在啮齿动物身上进行的实验将增进我们对可卡因对大脑功能的急性和慢性影响的理解，促进对项目 1 数据的解释，从而为理解人类可卡因成瘾的功能磁共振成像相关性和神经生物学后果提供重要的联系。