CLINICAL CIRCUITRY UNDERLYING METHAMPHETAMINE ADDICTION

甲基苯丙胺（METH）依赖在心理和身体方面具有严重后果， 健康，并给社区带来巨大的经济和法律的负担。甲基苯丙胺滥用和依赖，长期 这是西部的一个严重问题，现在正以接近流行病的比例蔓延到美国东部。 在过去的五年里，它在南卡罗来纳州经历了戏剧性的增长。线索引发的药物渴求 被认为是寻求毒品和在自然环境中复发的关键组成部分。调查人员 已经提出成瘾的一个关键特征是增加的线索显着性和增强的线索药物 记忆回路压倒了通常由前额叶皮层对自然线索施加的抑制控制 和调味品。METH治疗的药物开发正在取得进展，但仍有许多工作要做。 了解了甲基苯丙胺成瘾的基本神经生物学。提示曝光加上功能 神经成像技术（PET，SPECT，fMRI）在阐明大脑回路方面非常有用， 尼古丁、可卡因和酒精依赖者。有人建议，确定药理学 通过功能性脑成像测量改变人类线索诱导的渴望和药物寻求的药物 很可能是潜在药物的有效筛选工具， 药物开发 在临床前模型或人类临床成像中，不存在METH线索激活的电路图。 在啮齿动物中的临床前研究表明，METH治疗的动物可能具有受损的消退学习。 我们的研究小组使用功能磁共振成像技术来评估酒精对局部脑回路的影响， 最近，可卡因暗示刺激。与项目#1密切合作，其主要目标是 一项提议是开发程序，在线索产生的条件下，通过功能磁共振成像评估大脑回路。 非寻求治疗的METH依赖受试者的渴望和线索消退。使用BOLD fMRI，多个 随着时间的推移，将评估fMRI，以测量暴露于METH提示时回路激活的变化， 中性线索我们建议招募60名非寻求治疗的METH依赖男性和女性， 年龄在18至50岁之间的种族和民族群体参与这项研究。本研究将包括3 阶段：1）门诊筛查; 2）METH期间随时间推移重复fMRI的住院提示暴露， 中性线索暴露;和3）两周的门诊随访。该项目将与项目 #4在开发特定的METH环境线索方面，以及与#1项目在确定特定的 回路潜在的甲基线索反应性和灭绝。信息的双向交换， 在人类和动物研究中，确定参与这些重要功能的关键电路， 加快发现的步伐。

Methamphetamine (METH) dependence has drastic consequences in terms of psychological and physical health, and places great economic and legal burdens on communities. METH abuse and dependence, long a serious problem in the West, is now spreading in near-epidemic proportions to the eastern United States and has experienced dramatic growth in South Carolina in the past five years. Cue-elicited drug craving is believed to be a critical component in drug seeking, and relapse in the natural environment. Investigators have suggested that a critical characteristic of addiction is increased cue saliency and enhanced cue-drug memory circuits which overwhelm inhibitory control normally exerted by the prefrontal cortex for natural cues and reinforcers. Medication development for METH treatment is progressing, but much remains to be learned about the fundamental neurobiology of METH addiction. Cue exposure coupled with functional neuroimaging techniques (PET, SPECT, fMRI) has been extremely useful in elucidating brain circuitry for nicotine, cocaine, and alcohol-dependent individuals. It has been suggested that identifying pharmacologic agents that alter human cue-induced craving and drug-seeking as measured with functional brain imaging could well be an effective screening tool for potential pharmacotherapeutic agents and a productive path for drug development. No circuitry map exists for METH cue activation in either preclinical models or human clinical imaging. Preclinical studies in rodents indicate that METH-treated animals may have impaired extinction learning. Our group has used the technique of fMRI to evaluate regional brain circuitry changes with alcohol and, more recently, cocaine cue stimulation. Working in close concert with Project #1, the primary aims of this proposal are to develop procedures to assess brain circuitry through fMRI under conditions of cue-generated craving and cue extinction in non-treatment-seeking METH-dependent subjects. Using BOLD fMRI, multiple fMRIs will be assessed over time to measure changes in circuit activation with exposure to METH cues and neutral cues. We propose to recruit 60 non-treatment-seeking METH-dependent males and females of all ethnic and racial groups between ages 18 and 50 to participate in this study. This study will consist of 3 phases: 1) outpatient screening; 2) inpatient cue-exposure with repeated fMRIs overtime during METH and neutral cue exposure; and 3) Two weeks of outpatient follow-up. This project will work closely with Project #4 in the development of METH-specific environmental cues and with Project #1 in identifying specific circuits underlying METH cue-reactivity and extinction. The bidirectional exchange of information between human and animal studies in identifying the critical circuitry involved in these important functions will accelerate the pace of discovery.