FUNCTIONAL MRI OF HUMAN DRUG ABUSE

可卡因和尼古丁滥用仍然是当今社会的严重问题， 尽管有新的治疗方法，但再犯率仍然很高。 虽然 普遍认为，强有力的加强，在这种情况下， 可卡因，兴奋的特性，是主要负责 保持寻求毒品和吸毒行为，很少有人知道 神经生物学机制和这些药物的作用部位， 人类中枢神经系统（CNS）。 这些知识似乎是必要的， 最终开发出更成功的治疗策略。 作为 因此，该项目的总体目标是定义那些神经元 人体内调节尼古丁和可卡因作用的系统和回路 CNS，并确定这些站点的哪个子集参与其 戒断、渴望和强化的特性。 作为药理学 代理人，可卡因和尼古丁产生了一些深刻的行为和 生理效应。 来自动物模型的证据支持他们的观点。 与中皮质边缘（MCL）多巴胺系统的相互作用， 它们的增强性能。 然而，MCL系统的作用 这些药物在人体中的作用部位和方式几乎完全未知 由于非侵入性地解决这个问题的工具缺乏 必要的敏感性。 最后，人们认识到， CNS内的简单药理作用。 它们的强力兴奋剂 属性与环境线索配对， 被认为能够促进持续药物治疗的反应（CR） 使用并增加复发概率。 再一次，事实上， 关于它们的神经解剖学基底的知识。 它是假设 这些药物激活了大脑皮层和皮层下的终末区， MCLDA系统，这些区域也将被选择性地改变 在慢性药物使用期间，表现为系统功能的改变 在戒毒和渴望的过程中 的关系 脑电化学活动、血流量和葡萄糖代谢， 神经系统的功能代谢图是可能的， 功能性磁共振成像技术是一种非侵入性技术 成像是MRI的一个非常新的应用， 功能性大脑活动，而不使用X射线或电离 辐射 其出色的时间（秒）和空间（2-3毫米） 分辨率允许虚拟的“真实的时间”成像， 不可能与其他现有的程序。 该提案将利用 这种新的技术，以确定神经解剖部位的行动， 尼古丁和可卡因以及这些药物改变神经元的能力 当执行认知任务时， 神经元DA终末区。 我们还将研究 戒断和线索诱导的渴望对“休息”和 任务诱发的神经元激活。 我们还将讨论 大脑中的强化回路 希望这些数据 可能最终会导致更好地理解， 治疗毒瘾，反过来，减少再犯率。

Cocaine and nicotine abuse remain serious problems in today's society, and despite new treatments, recidivism rates remain high. While it is generally agreed that the powerful reinforcing and, in the case of cocaine, euphorigenic properties, are principally responsible for maintaining drug-seeking and drug-taking behavior, little is known about the neurobiological mechanisms and sites of action of these agents in the human central nervous system (CNS). Such knowledge appears necessary for the ultimate development of more successful treatment strategies. As such, the overall goal of this project is to define those neuronal systems and circuits mediating nicotine and cocaine actions in the human CNS and to determine which subset of these sites participate in their withdrawal, craving and reinforcing properties. As pharmacological agents, cocaine and nicotine produce a number of profound behavioral and physiological effects. Evidence from animal models support their interaction with the mesocorticolimbic (MCL) dopamine system in producing their reinforcing properties. However, both the role of the MCL system and where and how these drugs act in humans is almost completely unknown as the tools to noninvasively address this question have lacked the necessary sensitivity. Finally, it is recognized that drugs do not exert a simple pharmacological action within CNS. Their powerful stimulant properties become paired with environmental cues to form conditioned responses (CRs) which are thought to be able to promote continued drug use and increase relapse probability. Once again, virtually nothing is known regarding their neuroanatomic substrates. It is hypothesized that these agents activate cortical and subcortical terminal fields of the MCLDA system and that these regions will also be selectively altered during chronic drug use as manifest by alterations in system functioning during drug withdrawal and craving. With the relationship between cerebral electrochemical activity, blood flow and glucose metabolism, functional metabolic mapping of the nervous system is possible using a number of noninvasive techniques in man. Functional magnetic resonance imaging is a very new 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 (2-3 mm) resolution permits virtual 'real time' imaging and within subject designs not possible with other current procedures. This proposal will utilize this novel technique to determine the neuroanatomic sites of action of nicotine and cocaine and the ability of these drugs to alter neuronal responsivity when performing cognitive tasks believed to activate neuronal DA terminal regions. We will also examine the time course of withdrawal and the effects of cue-induced craving on both "resting" and task-induced neuronal activation. We will also address the question of reinforcement circuitry in the human brain. It is hoped that these data may eventually lead to better understanding of, and strategies for treating drug addiction, producing, in turn, a decrease in recidivism.