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Clinical and Experimental Human Sleep-Wake Pharmacogenetics

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Sleep-Wake Neurobiology and Pharmacology

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 253))

Abstract

Sleep and wakefulness are highly complex processes that are elegantly orchestrated by fine-tuned neurochemical changes among neuronal and non-neuronal ensembles, nuclei, and networks of the brain. Important neurotransmitters and neuromodulators regulating the circadian and homeostatic facets of sleep-wake physiology include melatonin, γ-aminobutyric acid, hypocretin, histamine, norepinephrine, serotonin, dopamine, and adenosine. Dysregulation of these neurochemical systems may cause sleep-wake disorders, which are commonly classified into insomnia disorder, parasomnias, circadian rhythm sleep-wake disorders, central disorders of hypersomnolence, sleep-related movement disorders, and sleep-related breathing disorders. Sleep-wake disorders can have far-reaching consequences on physical, mental, and social well-being and health and, thus, need be treated with effective and rational therapies. Apart from behavioral (e.g., cognitive behavioral therapy for insomnia), physiological (e.g., chronotherapy with bright light), and mechanical (e.g., continuous positive airway pressure treatment of obstructive sleep apnea) interventions, pharmacological treatments often are the first-line clinical option to improve disturbed sleep and wake states. Nevertheless, not all patients respond to pharmacotherapy in uniform and beneficial fashion, partly due to genetic differences. The improved understanding of the neurochemical mechanisms regulating sleep and wakefulness and the mode of action of sleep-wake therapeutics has provided a conceptual framework, to search for functional genetic variants modifying individual drug response phenotypes. This article will summarize the currently known genetic polymorphisms that modulate drug sensitivity and exposure, to partly determine individual responses to sleep-wake pharmacotherapy. In addition, a pharmacogenetic strategy will be outlined how based upon classical and opto-/chemogenetic strategies in animals, as well as human genetic associations, circuit mechanisms regulating sleep-wake functions in humans can be identified. As such, experimental human sleep-wake pharmacogenetics forms a bridge spanning basic research and clinical medicine and constitutes an essential step for the search and development of novel sleep-wake targets and therapeutics.

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Acknowledgments

The authors’ research has been supported by Swiss National Science Foundation, Zürich Center for Interdisciplinary Sleep Research, Clinical Research Priority Program “Sleep & Health” of the University of Zürich, Zürich Center for Integrative Human Physiology, Neuroscience Center Zürich, and Novartis Foundation for Medical-Biological Research (to HPL).

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland

    Hans-Peter Landolt

  2. Zürich Center for Interdisciplinary Sleep Research (ZiS), University of Zürich, Zürich, Switzerland

    Hans-Peter Landolt

  3. Neurobiology Research Unit and Neuropharm, Department of Neurology, Rigshospitalet, Copenhagen, Denmark

    Sebastian C. Holst

  4. Wisconsin Institute for Sleep and Consciousness, University of Wisconsin Madison, Madison, WI, USA

    Amandine Valomon

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  1. Hans-Peter Landolt
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  2. Sebastian C. Holst
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  3. Amandine Valomon
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Correspondence to Hans-Peter Landolt .

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  1. Human Sleep Psychopharmacology Laboratory, Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland

    Hans-Peter Landolt

  2. Surrey Sleep Research Centre, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK

    Derk-Jan Dijk

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Landolt, HP., Holst, S.C., Valomon, A. (2018). Clinical and Experimental Human Sleep-Wake Pharmacogenetics. In: Landolt, HP., Dijk, DJ. (eds) Sleep-Wake Neurobiology and Pharmacology . Handbook of Experimental Pharmacology, vol 253. Springer, Cham. https://doi.org/10.1007/164_2018_175

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