DRUG ABUSE, SLEEP AND COGNITION

只有当神经调节剂、睡眠和认知水平的变化之间的联系得到很好的描述和分析时，才能理解和有效地治疗药物滥用的许多功能失调方面。这一建议着重于两类药物的认知作用，精神兴奋剂（这里是可卡因）和选择性血清素再摄取抑制剂或SSRIs（这里是帕罗西汀），这两种药物都被认为能增强大脑的单胺能神经元系统。根据我们的基本神经生物学知识和睡眠和认知理论，我们已经对睡眠和神经调节因子介导可卡因滥用的认知影响产生了具体的预测。我们将把经过验证的动态睡眠监测仪Nightcap与认知测试结合起来，认知测试可以在分析睡眠测量的同一台Macintosh电脑上呈现和执行。该综合门诊系统的应用将使药物对睡眠和认知的影响的研究更加经济和自然。我们计划在两个独特的研究机构，哥伦比亚医学院物质使用研究中心的可卡因自我给药实验室和哈佛神经生理学睡眠实验室，使用这种动态监测能力来研究睡眠、单胺能机制及其相互作用如何介导可卡因滥用的认知后遗症。该建议的核心观点是，滥用单胺类药物，如可卡因，首先增强，然后损害觉醒-睡眠周期的神经调节动力学，最终对认知功能产生有害影响。我们提出了一系列理论驱动的研究，这些研究测试了特定的假设，这些假设将使我们能够分离和描述睡眠和单胺能神经调节剂对已知的可卡因使用和戒断的负面认知影响的相关影响。在一组七个补充方案中，我们将比较反复服用可卡因和戒断、服用帕罗西汀和停止服用帕罗西汀以及剥夺快速眼动睡眠对睡眠和认知表现的个人和综合影响。拟议中的研究将回答有关睡眠对认知的益处以及这些益处如何在药物滥用时丧失的基本问题。

Many dysfunctional aspects of drug abuse can be understood and effectively treated only when the links between changes in levels of neuromodulators, sleep, and cognition are well described and analyzed. This proposal focuses on the cognitive effects of two drug classes, the psychostimulants (here cocaine) and the selective serotonin reuptake inhibitors or SSRIs (here paroxetine), both of which are known to potentiate the monoaminergic neuronal systems of the brain. Drawing upon our basic neurobiological knowledge and theories of sleep and cognition, we have generated specific predictions on the sleep and neuromodulatory factors mediating the cognitive effects of cocaine abuse. We will combine our validated ambulatory sleep monitor, the Nightcap, with cognitive tests that can be presented and performed on the same Macintosh computer that analyzes sleep measurements. The study of drug effects on sleep and cognition will be made considerably more economical and naturalistic by the application of this integrated ambulatory system. We plan to use this ambulatory monitoring capability at two unique research facilities, the cocaine self-administration laboratory of the Substance Use Research Center at Columbia Medical School and the Harvard Laboratory of Neurophysiology sleep laboratory, to study how sleep, monoaminergic mechanisms, and their interactions may mediate the cognitive sequelae of cocaine abuse. At the heart of this proposal is the idea that the monoaminergic drugs of abuse such as cocaine, first potentiate but then later impair the neuromodulatory dynamics of the wake-sleep cycle with ultimately deleterious effects upon cognitive functioning. We propose a series of studies which are theory-driven and which test specific hypotheses that will allow us to isolate and describe the interrelated effects of sleep and monoaminergic neuromodulators on the known negative cognitive effects of cocaine use and abstinence. In a set of seven complementary protocols, we will compare the individual and combined effects on sleep and cognitive performance of repeated cocaine administration and abstinence, administration and discontinuation of paroxetine, and REM sleep deprivation. The proposed research will answer fundamental questions regarding the cognitive benefits of sleep and how these benefits are lost when drugs are abused.