Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.
Zürich Center of interdisciplinary Sleep Research, University of Zürich, Zürich, Switzerland.
Neuropsychopharmacology. 2018 Jun;43(7):1599-1607. doi: 10.1038/s41386-018-0018-8. Epub 2018 Feb 5.
Tolcapone, a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties, improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT. The impact of this common genetic variant on behavioral and neurophysiological markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of sleep homeostasis in humans. We first quantified in 73 young male volunteers the impact of COMT genotype on the evolution of attentional lapses during 40 h of extended wakefulness. Subsequently, we tested in an independent group of 30 young men whether selective inhibition of COMT activity with tolcapone counteracts attentional and neurophysiological markers of elevated sleep need in a genotype-dependent manner. Neither COMT genotype nor tolcapone affected brain electrical activity in wakefulness and sleep. By contrast, COMT genotype and tolcapone modulated the sleep loss-induced impairment of vigilant attention. More specifically, Val/Met heterozygotes produced twice as many lapses after a night without sleep than Met/Met homozygotes. Unexpectedly, tolcapone further deteriorated the sleep loss-induced performance deficits when compared to placebo, particularly in Val/Met and Met/Met genotypes. The findings suggest that PFC dopaminergic tone regulates sustained attention after sleep loss according to an inverse U-shape relationship, independently of neurophysiological markers of elevated sleep need.
托卡朋是一种穿透血脑屏障的儿茶酚-O-甲基转移酶（COMT）选择性抑制剂，没有精神刺激作用，可改善休息志愿者的认知和皮质信息处理能力，这取决于 COMT 的功能性 Val158Met 多态性的基因型。这种常见遗传变异对睡眠剥夺后增加睡眠需求的行为和神经生理标志物的影响存在争议。在这里，我们研究了托卡朋减轻睡眠剥夺对持续注意力失误的影响的潜在用途，并检验了多巴胺信号在人类前额叶皮层（PFC）中对睡眠稳态的神经行为和神经生理标志物有因果贡献的假设。我们首先在 73 名年轻男性志愿者中量化了 COMT 基因型对 40 小时延长清醒期间注意力失误演变的影响。随后，我们在 30 名年轻男性中进行了独立测试，以确定选择性抑制 COMT 活性的托卡朋是否以依赖基因型的方式对抗注意力和升高的睡眠需求的神经生理标志物。COMT 基因型和托卡朋既不影响清醒和睡眠时的脑电活动，也不影响。相比之下，COMT 基因型和托卡朋调节了睡眠剥夺引起的警惕注意力的损害。更具体地说，与 Met/Met 纯合子相比，Val/Met 杂合子在一夜无眠后产生的失误多出两倍。出乎意料的是，与安慰剂相比，托卡朋进一步恶化了睡眠剥夺引起的表现缺陷，尤其是在 Val/Met 和 Met/Met 基因型中。研究结果表明，PFC 多巴胺能张力根据反 U 型关系调节睡眠剥夺后的持续注意力，而与升高的睡眠需求的神经生理标志物无关。
