Institute of Pharmacology and Toxicology, University of Zürich, 8057 Zürich, Switzerland, Institute of Medical Molecular Genetics, University of Zürich, CH-8952 Schlieren, Switzerland, Zürich Center for Integrative Human Physiology, University of Zürich, 8057 Zürich, Switzerland, and Neuroscience Center Zurich, University of Zürich and ETH Zürich, 8057 Zürich, Switzerland.
J Neurosci. 2014 Jan 8;34(2):566-73. doi: 10.1523/JNEUROSCI.4128-13.2014.
While dopamine affects fundamental brain processes such as movement control, emotional responses, addiction, and pain, the roles for this neurotransmitter in regulating wakefulness and sleep are incompletely understood. Genetically modified animal models with reduced dopamine clearance exhibit hypersensitivity to caffeine, reduced-responsiveness to modafinil, and increased homeostatic response to prolonged wakefulness when compared with wild-type animals. Here we studied sleep-wake regulation in humans and combined pharmacogenetic and neurophysiologic methods to analyze the effects of the 3'-UTR variable-number-tandem-repeat polymorphism of the gene (DAT1, SLC6A3) encoding dopamine transporter (DAT). Previous research demonstrated that healthy homozygous 10-repeat (10R/10R) allele carriers of this genetic variant have reduced striatal DAT protein expression when compared with 9-repeat (9R) allele carriers. Objective and subjective estimates of caffeine sensitivity were higher in 10R allele homozygotes than in carriers of the 9R allele. Moreover, caffeine and modafinil affected wakefulness-induced changes in functional bands (delta, sigma, beta) of rhythmic brain activity in wakefulness and sleep in a DAT1 genotype-dependent manner. Finally, the sleep deprivation-induced increase in well established neurophysiologic markers of sleep homeostasis, including slow-wave sleep, electroencephalographic slow-wave activity (0.5-4.5 Hz), and number of low-frequency (0.5-2.0 Hz) oscillations in non-rapid-eye-movement sleep, was significantly larger in the 10R/10R genotype than in the 9R allele carriers of DAT1. Together, the data suggest that the dopamine transporter contributes to homeostatic sleep-wake regulation in humans.
虽然多巴胺影响基本的大脑过程，如运动控制、情绪反应、成瘾和疼痛，但这种神经递质在调节觉醒和睡眠中的作用还不完全清楚。与野生型动物相比，清除多巴胺减少的基因修饰动物模型对咖啡因敏感，对莫达非尼反应性降低，对长时间觉醒的体内平衡反应增加。在这里，我们研究了人类的睡眠-觉醒调节，并结合药理学遗传和神经生理方法来分析编码多巴胺转运体（DAT）的基因（DAT1，SLC6A3）的 3'-UTR 可变数量串联重复多态性的影响。先前的研究表明，这种遗传变异的健康纯合 10 重复（10R/10R）等位基因携带者的纹状体 DAT 蛋白表达减少与 9 重复（9R）等位基因携带者相比。与 9R 等位基因携带者相比，10R 等位基因纯合子对咖啡因敏感性的客观和主观估计更高。此外，咖啡因和莫达非尼以 DAT1 基因型依赖的方式影响觉醒诱导的功能带（δ、σ、β）的变化，在觉醒和睡眠中的节律性脑活动。最后，睡眠剥夺引起的睡眠内稳态的既定神经生理标志物的增加，包括慢波睡眠、脑电图慢波活动（0.5-4.5 Hz）和非快速眼动睡眠中低频（0.5-2.0 Hz）振荡的数量，在 10R/10R 基因型中比在 DAT1 的 9R 等位基因携带者中显著更大。总的来说，这些数据表明多巴胺转运体有助于人类的睡眠-觉醒内稳态调节。
