Neurochemical Substrates of Sleep Homeostasis

描述（由申请人提供）： 难以启动/维持睡眠困扰着多达30%的人口，但与睡眠和睡眠障碍相关的神经化学过程尚未明确确定。更好地了解脑电图慢波活动及其在睡眠丧失恢复中的作用，对于阐明稳态睡眠机制和阐明如何治疗睡眠障碍具有非常重要的意义。此外，睡眠障碍会导致吸毒复发，这些努力可能有助于解决这一严重的公共卫生问题。该研究的目的是通过评估睡眠中断产生的脑化学变化，确定完整和受损系统中睡眠机制的神经化学标志物。针对RFA-HL-01-009“睡眠与心脏、肺和血液疾病之间的相互关系”，我们提出了两个实验。首先，将在对照组和美沙酮维持受试者的基线、睡眠剥夺后和恢复睡眠后收集多导睡眠图（PSG）和磷磁共振波谱成像（31 P MRSI）。将在1个月和3个月时重复测量，以确定影响是否持续。在第二项实验中，将在急性戒断期间以及戒断后1个月和3个月从未用药的可卡因依赖和阿片类药物依赖受试者中收集PSG和31 P MRSI数据。由于这些组中睡眠障碍的戒断特征不同（分别为嗜睡与失眠），该实验将有助于描述改变大脑生物能量存在的条件。31 P MRSI可用于测量高能磷酸盐α-、γ-、β-NTP（ATP）的全局和局部变化。我们的试验数据显示，对照组受试者在睡眠剥夺后恢复后，β-NTP显著增加，磷脂分解代谢产物减少。在慢性阿片类药物依赖个体中观察到基线时的31 P MRS变化，但尚未在睡眠期间进行评估。据报道，阿片类药物滥用者和美沙酮维持患者存在慢性睡眠障碍，慢性阿片类药物滥用可能会损害稳态睡眠机制。我们假设美沙酮维持受试者的β-NTP会降低，并且在恢复后会表现出较小的慢波睡眠反弹和更适度的β-NTP增加或不增加。此外，随着时间的推移，这些受试者对睡眠剥夺的神经化学反应将接近对照组，b-NTP将在可卡因戒断期间增加，而在阿片类药物戒断期间减少，反映出它们在这段时间内对睡眠的不同影响。总的来说，这些研究可以确定睡眠恢复功能的神经化学标志物，从而增强我们对基本睡眠机制的理解，并可能导致药物滥用和普通人群中睡眠障碍的新的和改进的治疗方法。

DESCRIPTION (provided by applicant): Difficulty initiating/maintaining sleep afflicts up to 30% of the population, yet the neurochemical processes associated with sleep and sleep disturbances have not been clearly identified. A better understanding of EEG slow-wave activity and its role in recovery from sleep loss could be invaluable in elucidating the homeostatic sleep mechanism and shedding light on how to treat disturbed sleep. Further, sleep disturbances contribute to relapse to drug use and such efforts might help address this serious public health problem. The purpose of the study is to identify neurochemical markers of sleep mechanism in an intact and an impaired system, by evaluating changes in brain chemistry produced by disrupted sleep. In response to RFA-HL-01-009, "Interrelationship between sleep and heart, lung, and blood diseases" we propose two experiments. In the first, polysomnography (PSG) and phosphorous magnetic resonance spectroscopic imaging (31P MRSI) will be collected at baseline, after sleep deprivation, and after recovery sleep in controls and in methadone-maintained subjects. Measures will be repeated at 1 and 3 months to determine if the effects persist. In the second experiment, PSG and 31P MRSI data will be collected from unmedicated cocaine-dependent and opiate-dependent subjects during acute withdrawal and at 1 and 3 months post withdrawal. As the abstinence profile for sleep disturbance differs in these groups (hypersomnia vs insomnia, respectively) this experiment will help delineate the conditions under which altered brain bioenergenics exist. 31P MRSI can be used to measure global and focal changes in high energy phosphate alpha-,gamma-,beta-NTP (ATP). Our pilot data showed significant increases in beta-NTP and decreases in phospholipid catabolite production after recovery following sleep deprivation in control subjects. 31P MRS changes have been observed in chronic opiate-dependent individuals at baseline, but have not been evaluated during sleep. Chronic sleep disturbances have been reported in opiate abusers and methadone-maintained patients and the homeostatic sleep mechanisms may be impaired in chronic opiate abuse. We hypothesize that methadone-maintained subjects will have decreased beta-NTP and will exhibit smaller slow wave sleep rebound and a more modest or no increase in beta-NTP after recovery. Further, the neurochemical response to sleep deprivation in these subjects will approach that of controls over time b-NTP will increase during cocaine withdrawal and decrease during opiate withdrawal, reflecting their differential effects on sleep during this time. Collectively, these studies may identify neurochemical markers for the recovery function of sleep, thus enhancing our understanding pf basic sleep mechanisms and potentially leading to new and improved treatments for sleep disturbances in both the substance-abusing and general population.