Functional Brain Mapping of Cocaine Action

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，但在了解可卡因和其他滥用药物如何对大脑产生急性和慢性作用方面仍然难以取得进展。非侵入性功能成像技术的发展提供了敏感和日益具体的手段，神经过程可以研究与高空间和时间分辨率。基于在发现的前五年中开发的方法和获得的结果，在项目3的竞争性更新中提出的实验侧重于信息啮齿动物模型，利用慢性可卡因自我给药大鼠，三种基因敲除小鼠以及药物幼稚对照。我们建议使用功能性磁共振成像（fMRI），激光多普勒血流仪，2-DG代谢图，并在体内微透析方法来研究可卡因的作用机制的实验。具体目标1研究脑奖赏回路中多巴胺能活动与fMRI信号产生之间的联系，并探索多巴胺能和GABA能系统在调节该活动中的作用。具体目标2利用功能性磁共振成像在小鼠中，其中编码多巴胺转运蛋白或D1 a受体或5-HT 1b受体的基因已被赋予。我们预期这些实验的结果将为特定目标1中提出的药理学实验提供确证性证据，确定有助于可卡因诱导脑激活的多巴胺能和多巴胺能信号转导的特定分子组分的作用。基于特定目标1的结果，特定目标3研究了多巴胺能和多巴胺能系统在长期适应中的作用，长期适应是使用可卡因自我给药范式（目前可用的最接近人类物质滥用的动物模型）的慢性可卡因暴露的结果。我们在项目1中提出的使用最先进的功能成像技术的假设驱动的实验，与项目2中提出的实验相一致，重点是识别将精神兴奋剂给药与脑血管反应耦合的机制，旨在更深入地了解可卡因的作用机制。这些啮齿动物实验将促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fMRI相关性和神经生物学后果提供关键联系。

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.