Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT.
OBJECTIVE
Modafinil may promote wakefulness by increasing cerebral dopaminergic neurotransmission, which importantly depends on activity of catechol-O-methyltransferase (COMT) in prefrontal cortex. The effects of modafinil on sleep homeostasis in humans are unknown. Employing a novel sleep-pharmacogenetic approach, we investigated the interaction of modafinil with sleep deprivation to study dopaminergic mechanisms of sleep homeostasis.


METHODS
Placebo-controlled, double-blind, randomized crossover study.


METHODS
Sleep laboratory in temporal isolation unit.


METHODS
22 healthy young men (23.4 +/- 0.5 years) prospectively enrolled based on genotype of the functional Val158Met polymorphism of COMT(10 Val/Val and 12 Met/Met homozygotes).


METHODS
2 x 100 mg modafinil and placebo administered at 11 and 23 hours during 40 hours prolonged wakefulness.


RESULTS
Subjective sleepiness and EEG markers of sleep homeostasis in wakefulness and sleep were equally affected by sleep deprivation in Val/Val and Met/Met allele carriers (placebo condition). Modafinil attenuated the evolution of sleepiness and EEG 5-8 Hz activity during sleep deprivation in both genotypes. In contrast to caffeine, modafinil did not reduce EEG slow wave activity (0.75-4.5 Hz) in recovery sleep, yet specifically increased 3.0-6.75 Hz and > 16.75 Hz activity in NREM sleep in the Val/Val genotype of COMT.


CONCLUSIONS
The Val158Met polymorphism of COMT modulates the effects of modafinil on the NREM sleep EEG in recovery sleep after prolonged wakefulness. The sleep EEG changes induced by modafinil markedly differ from those of caffeine, showing that pharmacological interference with dopaminergic and adenosinergic neurotransmission during sleep deprivation differently affects sleep homeostasis.
Bodenmann
Sereina
S
Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.
Landolt
Hans-Peter
HP
D000483:Alleles; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects*; D005583:Fourier Analysis; D006580:Genetic Carrier Screening; D005838:Genotype; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D000077408:Modafinil; D011110:Polymorphism, Genetic / Q000235:genetics*; D017397:Prefrontal Cortex / Q000187:drug effects; D011446:Prospective Studies; D012815:Signal Processing, Computer-Assisted; D012892:Sleep Deprivation / Q000235:genetics*; D012894:Sleep Stages / Q000187:drug effects / Q000235:genetics; D014851:Wakefulness / Q000187:drug effects / Q000235:genetics; D055815:Young Adult
D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D002394:Catechol O-Methyltransferase; D000077408:Modafinil
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