PET Studies of the SERT and DAT in METH Users

描述(申请人提供)：流行的娱乐滥用药物甲基苯丙胺(冰毒)，有可能破坏各种实验动物的大脑5-羟色胺(5-羟色胺)和多巴胺(DA)轴突终末，包括各种非人类灵长类物种。来自一项PET研究和最近对慢性冰毒使用者的尸检分析的证据表明，人类也容易受到冰毒诱导的5-羟色胺神经毒性的影响。冰毒诱导的5-羟色胺神经毒性与多巴胺神经毒性的相对严重程度仍有待确定。鉴于大脑5-羟色胺神经元在认知功能和睡眠中的重要作用，确定大脑5-羟色胺神经毒性是否可能在许多研究人员报告的冰毒使用者的认知功能障碍中发挥作用，或者在我们最近记录的戒除冰毒使用者的睡眠异常中发挥作用，是非常有意义的。该项目的目的是确定在禁欲冰毒使用者中冰毒诱导的DA和5-羟色胺神经毒性的相对严重程度，并全面描述相同个体的睡眠异常。该项目的次要目标是探索冰毒引起的大脑单胺能标志物减少与冰毒使用者认知和睡眠改变之间的关系。更好地了解冰毒对人类的长期神经毒性影响，可能会导致针对冰毒滥用和依赖的更多和更有针对性的药物治疗方法。本项目的三个主要目标是：1)通过正电子发射断层扫描(PET)测量戒毒者和健康对照组的5-羟色胺转运体(SERT)和多巴胺转运体(DAT)结合电位(BP)，以[11C]DASB和[11C]MPH作为放射性配基，同时评估戒毒者大脑中5-羟色胺和多巴胺神经元的状态；2)获得并比较这些受试者的睡眠多导描记指标；3)获得并比较这些受试者的正式神经精神病学(认知)测量，并探索认知表现与目标1中获得的SERT和DAT的PET标记物之间的潜在关系。第四，探索性的目的是：4)评估戒毒者和对照组的睡眠、认知和DAT和SERT的PET标记物之间的潜在关系。这项拟议的研究将首次同时评估戒毒者5-羟色胺和多巴胺神经元的脑标志物，获得戒毒者的正式睡眠多导图测量，并探索同一个体中DAT和SERT的脑标志物与认知和睡眠异常的关系。 公共卫生相关性：本项目的总体目标是使用最先进的成像、多导睡眠和行为方法来阐明甲基苯丙胺(冰毒)滥用和依赖的神经生物学和行为后果。

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.