Functional Brain Mapping of Cocaine Action

虽然可卡因的获取和使用继续对公众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为以高空间和时间分辨率研究神经过程提供了灵敏和日益特异的手段。在最初五年发现的方法和结果的基础上，在项目3的竞争性更新中提出的实验重点是提供信息的啮齿动物模型，利用慢性可卡因自我给药的大鼠、三种基因敲除小鼠以及药物未成熟的对照。我们建议使用功能磁共振成像(FMRI)、激光多普勒血流计、2-DG代谢图谱和体内微透析方法来研究可卡因的作用机制。具体目的1研究大脑奖赏回路中的多巴胺能活动与fMRI信号产生之间的联系，并探索5-羟色胺能和GABA能系统在调节这一活动中的作用。特定目的2利用功能磁共振成像在编码多巴胺转运体或D1a受体或Th4e 5-HT1B受体的基因已不起作用的小鼠中进行。我们预计，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证据，确定多巴胺和5-羟色胺能信号转导的特定分子成分在可卡因诱导的大脑激活中的作用。在特定目标1结果的基础上，特定目标3利用可卡因自我给药范式，研究了多巴胺能和5-羟色胺能系统在长期适应中的作用，这种适应是由于慢性可卡因暴露而发生的，可卡因自我给药范式是目前可用的最接近人类物质滥用的动物模型。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中提出的实验相结合，专注于识别心理刺激剂给药与脑血管反应之间的耦合机制，旨在提供对可卡因作用机制的更深层次的理解。这些在啮齿动物身上的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，有助于解释项目1的数据，从而为理解可卡因成瘾对人类的功能磁共振相关和神经生物学后果提供关键的联系。

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.