PET Studies of the SERT and DAT in METH Users

描述（由申请人提供）：甲基苯丙胺（METH）是一种流行的滥用娱乐性药物，在多种实验动物（包括各种非人类灵长类动物）中具有破坏脑5-羟色胺（5-HT）和多巴胺（DA）轴突末端的潜力。来自一项PET研究的证据以及最近对慢性冰毒使用者的尸检分析表明，人类也容易受到冰毒诱导的5-HT神经毒性的影响。甲基苯丙胺诱导的5-HT神经毒性与DA神经毒性的相对严重程度仍有待确定。鉴于脑5-HT神经元在认知功能和睡眠中的重要作用，确定脑5-HT神经毒性是否可能在许多研究者报道的冰毒使用者的认知功能障碍中起作用，或者在我们最近记录的戒断冰毒使用者的睡眠异常中起作用，这是非常有意义的。该项目的目的是确定冰毒戒断服用者中冰毒诱导的DA和5-HT神经毒性的相对严重程度，并充分表征同一个体的睡眠异常。该项目的第二个目的是探索冰毒使用者大脑单胺能标记物减少与认知和睡眠改变之间的关系。更好地了解甲基苯丙胺对人类的长期神经毒性作用，可能会导致对甲基苯丙胺滥用和依赖的额外和改进的靶向药物治疗方法。该项目的三个主要目的是：1)通过使用正电子发射断层扫描（PET）测量戒断冰毒使用者和健康对照者的5-HT转运体（SERT）和DA转运体（DAT）结合电位（BP），以[11C] DASB和[11C] MPH作为放射配体，同时评估戒断冰毒使用者大脑5-HT和DA神经元的状态；2)获取并比较相同受试者组的睡眠多导睡眠图测量结果；3)获得并比较这些相同受试者组的正式神经精神（认知）测量，并探索认知表现与Aim 1中获得的SERT和DAT的PET标记之间的潜在关系。第四个探索性目的是：4)评估戒断冰毒使用者和对照组中睡眠、认知、DAT和SERT的PET标记物之间的潜在关系。该研究将首次同时评估戒断冰毒吸食者的5-HT和DA神经元的脑标记物，获得戒断冰毒吸食者的正式睡眠多导睡眠图测量，并探索同一个体中DAT和SERT脑标记物与认知和睡眠异常的关系。

DESCRIPTION (provided by applicant): The popular recreational drug of abuse, methamphetamine (METH), has the potential to destroy brain serotonin (5-HT) and dopamine (DA) axon terminals in a variety of experimental animals, including various non-human primate species. Evidence from a single PET study and, more recently, post mortem analyses in chronic METH users indicate that humans are also susceptible to METH-induced 5-HT neurotoxicity. The relative severity of METH-induced 5-HT neurotoxicity versus DA neurotoxicity remains to be determined. Given the important role of brain 5-HT neurons in cognitive function and sleep, it is of significant interest to determine whether brain 5-HT neurotoxicity may play a role in cognitive dysfunction in METH users that has been reported by many investigators, or in sleep abnormalities that we have recently documented in abstinent METH users. The purpose of this project is to determine the relative severity of METH-induced DA and 5-HT neurotoxicity in abstinent METH users, and to fully characterize sleep abnormalities in the same individuals. Secondary aims of this project are to explore the relationship between METH-induced reductions in brain monoaminergic markers and alterations in cognition and sleep in METH users. A better understanding of the long-term neurotoxic effects of METH in humans could lead to additional and improved targeted pharmacotherapeutic approaches for METH abuse and dependence. The three primary aims of this project are: 1) To concomitantly assess the status of brain 5-HT and DA neurons in abstinent METH users by using positron emission tomography (PET) to measure 5-HT transporter (SERT) and DA transporter (DAT) binding potentials (BP) in abstinent METH users and healthy controls employing [11C] DASB and [11C] MPH as radioligands; 2) To obtain and compare sleep polysomnographic measures in these same subject groups and; 3) To obtain and compare formal neuropsychiatric (cognitive) measures in these same subject groups, and explore potential relationships between cognitive performance and PET markers of the SERT and DAT obtained in Aim 1. A fourth, exploratory, aim is: 4) To assess the potential relationships between measures of sleep, cognition, and PET markers of the DAT and SERT in abstinent METH users and controls. The proposed research will be the first to simultaneously evaluate brain markers of 5-HT and DA neurons in abstinent METH users, to obtain formal sleep polysomnographic measures in abstinent METH users, and to explore the relationship of brain markers of the DAT and SERT to cognitive and sleep abnormalities in the same individuals. PUBLIC HEALTH RELEVANCE: The overall goal of the present project is to uses state-of-the-art imaging, polysomnographic and behavioral methods to elucidate the neurobiological and behavioral consequences of methamphetamine (METH) abuse and dependence.