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Hans Peter Landolt"Sleep deprivation, stimulants, and performance"

Abstract :

It is well established that enough and undisturbed sleep is indispensible for personal well-being and the ability to perform properly.
Nevertheless, the exact function(s) of sleep remain unknown. In addition, the subjective and objective responses to sleep- and wakefulness-modifying medications are highly variable among individuals. Human sleep pharmaco-genetics provides a powerful new approach, to elucidate molecular mechanisms of sleep-wake regulation and to identify new treatments of disturbances of sleep and vigilance. We demonstrated that a common genetic variation in the A2A receptor gene (ADORA2A) contributes to individual sensitivity to the effects of caffeine on sleep. Subsequent studies showed that a distinct combination of ADORA2A alleles (referred to as haplotype HT4) modulates recovery sleep after caffeine intake during prolonged wakefulness. Compared to other ADORA2A haplotype alleles, the HT4 haplotype was also associated with better performance on the psychomotor vigilance task - a current gold standard measurement of sustained vigilant attention. On the other hand, caffeine failed to mitigate the waking-induced impairment of sustained attention in HT4 haplotype allele carriers, whereas modafinil improved it irrespectively of ADORA2A haplotype. Modafinil is thought to promote wakefulness by increasing cerebral dopaminergic neurotransmission, which importantly depends on activity of catechol-O-methyl¬transferase (COMT). A functional Val158Met substitution of COMT is associated with reduced activity of this enzyme. We quantified modafinil-induced changes on the effects of sleep loss in homozygous Val/Val and Met/Met allele carriers of COMT. Modafinil improved subjective state and sustained attention after prolonged wakefulness in COMT genotype-specific manner. Taken together, these studies highlight the importance of genetic factors for pharmacological effects on sleep-wake regulation. The findings show that different stimulants interact differently with sleep and suggest that distinct mechanisms underlie sleep loss-induced changes in sleep, subjective state, and waking performance. It is envisaged that an integrative, sleep pharmaco-genetic approach could lead to evidence-based novel treatments of sleep-wake pathologies and, possibly, to improvement of sleep-associated brain functions.

Selected publications

Bodenmann S, Landolt HP. Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT and differ from those of caffeine. Sleep 33, 1027 -035 (2010)
Bodenmann S, Rusterholz T, Dürr R, Stoll C, Bachmann V, Geissler E, Jaggi-Schwarz K and Landolt HP. The Functional Val158Met Polymorphism of COMT Predicts Inter-individual Differences in Brain Alpha Oscillations in Young Men. J Neurosci 29: 10855-10862 (2009)
Bodenmann S, Xu S, Luhmann UFO, Arand M, Berger W, Jung HH and Landolt HP Pharmacogenetics of modafinil after sleep loss: Catechol-O-methyltransferase genotype modulates waking functions but not recovery sleep. Clin Pharmacol Ther 85 (2009)

Scientific focus :

An hourglass mechanism keeping track of wakefulness and sleep ("sleep homeostasis") and an endogenous oscillator with a period of approximately one day (lat. "circadian" = roughly one day) interact to regulate wakefulness and sleep. Our primary research is in the physiology and pharmacology of wake-sleep functions focusing on homeostatic sleep regulation in healthy volunteers and patients suffering from psychiatric and neurological disorders. We use a multidisciplinary, integrative approach combining state-of-the-art methods of pharmacogenetics, electroencephalography (EEG), brain imaging and neurocognitive testing to address open questions related to the physiological processes and neurochemical mechanisms regulating wakefulness and sleep in health and disease.

Pierre Philip directeur de l'USR CNRS 3413 SANPSY