How to Keep the Brain Awake? The Complex Molecular Pharmacogenetics of Wake Promotion

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 similar to 2Hz 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. Neuropsychopharmacology (2009) 34, 1625-1640; doi:10.1038/npp.2009.3; published online 4 February 2009