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Clinical Trial
, 43 (7), 1599-1607

Effects of COMT Genotype and Tolcapone on Lapses of Sustained Attention After Sleep Deprivation in Healthy Young Men

Affiliations
Clinical Trial

Effects of COMT Genotype and Tolcapone on Lapses of Sustained Attention After Sleep Deprivation in Healthy Young Men

Amandine Valomon et al. Neuropsychopharmacology.

Abstract

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.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Lapses of attention (i.e., trials on a 10-min PVT with reaction times >500 ms, expressed as a percentage of all trials in a quintile) across 40 h of sustained wakefulness, split by COMT genotypes. A PVT lapses (y-axis) as a function of time on task (z-axis) and time awake (x-axis). The warmer the colors, the higher the lapse frequency. The 3D plots are split by COMT genotypes (left panel: Val/Val; middle panel: Val/Met; right panel: Met/Met). B Comparison of lapse frequencies in baseline (day 1) and after sleep deprivation (day 2), split by COMT genotypes (Val/Val: red line; Val/Met: black line; Met/Met: blue line). Values represent estimated means ± standard error; pvalue (p < 0.0006) withstands Bonferroni correction (p < 0.016)
Fig. 2
Fig. 2
The increase in attentional lapses on a 10-min PVT after sleep deprivation is exacerbated by the COMT inhibitor tolcapone and modulated by COMT genotype. A Average lapse frequencies after sleep deprivation (day 2) in placebo (white) and tolcapone (black) conditions. Bars represent means ± SEM (n = 30). B Evolution of lapse frequency on the PVT, split by treatment (placebo: open circles; tolcapone: filled circles) and genotype (Val/Val: red; Val/Met: black; Met/Met: blue). Estimated means ± standard error (n = 10 per group). Tolcapone administration is indicated with vertical lines. *p < 0.0004 (tolcapone vs. placebo; withstanding Bonferroni correction)
Fig. 3
Fig. 3
The homeostatic build-up in sleep pressure is indistinguishable among COMT genotypes and not affected by tolcapone. A Evolution of 1–9 Hz activity in the waking EEG across 40 h prolonged wakefulness. EEG activity in placebo (open circles) and tolcapone (filled circles) conditions was expressed as a percentage of the mean values at 08:00, 11:00, 14:00, and 17:00 on the baseline day (dashed horizontal line), split by COMT genotypes (Val/Val: red line; Val/Met: black line; Met/Met: blue line). Administration of tolcapone at 7:00 and 07:00 is indicated with capsule and vertical dashed lines. Three-way mixed-model ANOVA with the factors “genotype,” “treatment,” and “time” yielded significant effects of “time,” yet no significant effects and interactions with “genotype” or “treatment” (see main text). B Dynamics of mean SWA across NREM sleep episodes 1–4 in baseline (mean of two baseline nights) and recovery nights. EEG activity (means ± SEM) in placebo (open circles) and tolcapone conditions (filled circles) was expressed as a percentage of the mean all-night values in baseline (dashed horizontal line), split by COMT genotypes (Val/Val: red line; Val/Met: black line; Met/Met: blue line). Three-way mixed-model ANOVA with the factors “genotype,” “condition,” and “NREM sleep episodes” yielded significant effects of “episode,” “condition,” and “cycle” x “condition,” yet no significant interactions involving “genotype” (see main text). Values represent estimated means ± standard error. *p < 0.05 (tolcapone recovery vs. mean baseline; paired, two-tailed t tests). +p < 0.05 (placebo recovery vs. mean baseline; paired, two-tailed ttests)
Fig. 4
Fig. 4
Schematic illustration of the proposed relationships between PFC dopamine transmission and attentional lapses in baseline (green shading), after sleep deprivation (orange shading), and after sleep deprivation and tolcapone administration (yellow shading), split by COMT genotypes (Val/Val: red; Val/Met: black; Met/Met: blue). The data suggest an inverse U-shaped relationship between PFC dopamine transmission and lapse frequency. While the increase in PFC dopamine transmission with sleep deprivation may be relatively more pronounced in Val/Val than in Val/Met and Met/Met allele carriers, tolcapone reduces COMT activity to roughly the same level in all three genotypes [13]. Asterisks indicate impacts of genotype and tolcapone treatment after sleep deprivation. SD: sleep deprivation study, SD&T: sleep deprivation and tolcapone study. See Discussion for details

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