Abstract
Wake-promoting drugs are widely used to treat excessive daytime sleepiness. The neuronal pathways involved in wake promotion are multiple and often not well characterized. We tested d-amphetamine, modafinil, and YKP10A, a novel wake-promoting compound, in three inbred strains of mice. The wake duration induced by YKP10A and d-amphetamine depended similarly on genotype, whereas opposite strain differences were observed after modafinil. Electroencephalogram (EEG) analysis during drug-induced wakefulness revealed a transient ∼2 Hz slowing of theta oscillations and an increase in beta-2 (20–35 Hz) activity only after YKP10A. Gamma activity (35–60 Hz) was induced by all drugs in a drug- and genotype-dependent manner. Brain transcriptome and clustering analyses indicated that the three drugs have both common and specific molecular signatures. The correlation between specific EEG and gene-expression signatures suggests that the neuronal pathways activated to stay awake vary among drugs and genetic background.
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Acknowledgements
We thank V Calpini, S Tawffik, K Harshman, and O Hagenbuchle, and the staff of the Lausanne DNA array facility for their expert technical assistance. This study was supported by a research grant from Johnson and Johnson, Beerse, Belgium, and the University of Lausanne, Switzerland.
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MT declares that over the past 3 years he has received compensation from UCB Pharma and Servier. AA and WD declare their full-time employment at Johnson and Johnson, Pharmaceutical Research and Development, Beerse, Belgium. SH, SP, and PF declare that, except for income received from their primary employers, no financial support or compensation has been received from any individual or corporate entity over the past 3 years of research or professional service, and they have no personal financial holdings that could be perceived as constituting a potential conflict of interest.
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Hasan, S., Pradervand, S., Ahnaou, A. et al. How to Keep the Brain Awake? The Complex Molecular Pharmacogenetics of Wake Promotion. Neuropsychopharmacol 34, 1625–1640 (2009). https://doi.org/10.1038/npp.2009.3
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DOI: https://doi.org/10.1038/npp.2009.3
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