DRUG ABUSE, SLEEP AND COGNITION

只有当很好地描述和分析神经调节剂、睡眠和认知水平变化之间的联系时，药物滥用的许多功能障碍方面才能被理解和有效地治疗。这项建议侧重于两类药物的认知影响，精神刺激剂(这里是可卡因)和选择性5-羟色胺再摄取抑制剂(这里是帕罗西汀)，这两种药物都已知可以增强大脑的单胺能神经元系统。利用我们的基本神经生物学知识和睡眠和认知理论，我们已经产生了对睡眠和神经调节因素的具体预测，这些因素介导了可卡因滥用的认知影响。我们将把我们经过验证的动态睡眠监测器--睡帽--与认知测试结合起来，这些测试可以在分析睡眠测量数据的同一台Macintosh电脑上呈现和执行。通过应用这一集成的非卧床系统，药物对睡眠和认知的影响的研究将变得更加经济和自然。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管理实验室和哈佛大学神经生理学睡眠实验室--使用这种动态监测能力，以研究睡眠、单胺类机制及其相互作用如何调节可卡因滥用的认知后遗症。这一提议的核心是这样一种观点，即滥用的单胺类药物，如可卡因，首先会增强唤醒-睡眠周期的神经调节动力学，最终会对认知功能产生有害影响。我们提出了一系列以理论为导向的研究，并测试了特定的假设，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除的负面认知影响的相互关联的影响。在一组七个互补的方案中，我们将比较重复服用可卡因和禁欲、服用和停用帕罗西汀以及快速眼动睡眠剥夺对睡眠和认知表现的单独和联合影响。这项拟议的研究将回答有关睡眠的认知益处以及滥用药物时这些益处是如何丧失的基本问题。

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.