EFFECTS OF THC ON REGIONAL BRAIN ACTIVITY--A FMRI STUDY

THC 对区域大脑活动的影响——一项 FMRI 研究

• 批准号: 6287650
• 负责人: ALAN S BLOOM
• 金额: $ 32.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-29 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6287650
• 关键词: bioimaging /biomedical imaging; cannabinoids; cardiovascular pharmacology; cerebrovascular system; clinical research; cognition; drug withdrawal; functional magnetic resonance imaging; human subject; marijuana abuse; neuropharmacology; pharmacokinetics; psychomotor function; psychopharmacology

DESCRIPTION: (Adapted from applicant's abstract): The use of marijuana by young people in our society continues to be a problem. It is the illicit drug that is most commonly used by youths today. Estimates of worldwide regular users exceed one hundred million individuals. However we still know little of the neurobiological consequences of its use by humans. It is clear that a better understanding of its actions in the human brain will benefit the development of innovative methods to deal with the increase in marijuana use and abuse. At present, functional sites for the action of marijuana in the human brain are poorly understood. As a result of significant technological advances in human functional brain imaging, it is now possible to directly examine the effects of marijuana and its chronic use on the human brain. The long range goal of this project is to elucidate sites of action A9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, in human brain and to determine those that are mechanistically related to the drug's intoxicating and self-administration properties and its impairment of cognitive and perceptual motor behavior. This project will be conducted entirely on experienced human marijuana users. Functional magnetic resonance imaging (FMRI) will be used as the imaging modality in all studies. fMRI is a specialized application of MRI that permits an examination of functional cerebral activity without the use of X-rays or ionizing radiation. Its excellent temporal (seconds) and spatial (2-4 mm) resolution permits virtual "real time' brain imaging and within subjects designs that are not possible with other current non-invasive or minimally invasive procedures. This project has four specific aims: 1) To determine the neuronal and non-neuronal (vascular) mechanisms underlying the changes in fMRl signal induced by A9-THC. This will be accomplished by using both arterial spin labeling based perfusion studies and first pass Gd-DTPA blood volume mapping. These results will expand our basic understanding of the dynamics of cannabinoid effects on brain neuronal and vascular function and will be applied to the analysis and interpretation of the studies from Aims 2, 3 and 4. 2) To further quantify A9-THC action using BOLD imaging to determine its pharmacodynamic properties within the human brain and to relate them in time and intensity to observed physiological and behavioral actions of intravenous ^9-THC. 3) To determine the ability of ^9-THC to aRer functional brain activity using perceptual-motor and cognitive tasks that activate specific brain regions containing cannabinoid receptors as experimental probes. 4) To determine the effects of heavy, chronic marijuana use and cessation on regional neuronal responsivity by comparing neuronal responses to task activation and acute drug challenge as a function of use and/or withdrawal. It is proposed that THC produces distinct changes in the activity of the human brain, both at rest and during the performance of cognitive and perceptual-motor tasks that are measurable using fMRl measures of blood oxygenation, flow and volume, It is further hypothesized that the unique behavioral and physiological effects of THC and marijuana in humans is due to unique patterns of brain regions activated and/or inhibited following acute drug administration, and that these responses will be both dose and time specific. The successful completion of these studies will increase our knowledge of the locus of marijuana action in humans and may indicate new strategies for dealing with its increasing use in our youth.

描述：（改编自申请人的摘要）：年轻人吸食大麻的情况 我们社会中的人们仍然是一个问题。这是违禁药物 当今年轻人最常用的。全球普通用户估计超过 一亿人。然而我们对此仍知之甚少 人类使用它的神经生物学后果。显然，更好的 了解其在人脑中的作用将有利于人类大脑的发展 应对大麻使用和滥用增加的创新方法。在 目前，大麻在人脑中发挥作用的功能位点是 不太了解。由于人类技术的重大进步 功能性脑成像，现在可以直接检查 大麻及其对人脑的长期使用。本次活动的长远目标 该项目旨在阐明 A9-四氢大麻酚 (THC) 的作用位点， 大麻在人脑中的主要精神活性成分并确定 那些在机制上与药物的致醉性和作用相关的 自我管理特性及其对认知和知觉的损害 运动行为。该项目将完全由经验丰富的人员进行 大麻使用者。功能磁共振成像（FMRI）将被用作 所有研究中的成像方式。 fMRI 是 MRI 的专门应用 允许在不使用 X 射线或电离辐射。其出色的时间（秒）和空间（2-4 mm) 分辨率允许在受试者体内进行虚拟“实时”大脑成像 当前其他无创或微创设计无法实现的设计 侵入性操作。该项目有四个具体目标： 1) 确定 fMRl 变化背后的神经元和非神经元（血管）机制 A9-THC 诱导的信号。这将通过使用动脉旋转来完成 基于标记的灌注研究和首次通过 Gd-DTPA 血容量图。 这些结果将扩展我们对动力学的基本理解 大麻素对大脑神经元和血管功能的影响并将被应用 对目标 2、3 和 4 的研究进行分析和解释。 2) 使用 BOLD 成像进一步量化 A9-THC 作用以确定其 人脑内的药效学特性并及时将它们联系起来 和观察到的静脉注射生理和行为作用的强度 ^9-四氢大麻酚。 3) 确定^9-THC对大脑功能活动的影响 使用激活特定大脑区域的感知运动和认知任务 含有大麻素受体作为实验探针。 4) 确定 大量、长期吸食和戒断大麻对区域神经元的影响 通过比较神经元对任务激活和急性药物的反应来评估反应性 挑战作为使用和/或退出的函数。建议 THC 无论是在休息还是在休息时，都会对人脑的活动产生明显的变化 在执行认知和知觉运动任务期间 可使用 fMRl 测量血氧、流量和容量进行测量， 进一步假设独特的行为和生理效应 人类的四氢大麻酚和大麻是由于大脑区域的独特模式造成的 急性给药后被激活和/或抑制，并且这些 反应将具有剂量和时间特异性。顺利完成 这些研究将增加我们对大麻作用轨迹的了解 人类并可能提出新的策略来应对其日益增加的使用 我们的青春。