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 approximately 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.
Hasan
Sibah
S
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Pradervand
Sylvain
S
Ahnaou
Abdellah
A
Drinkenburg
Wilhelmus
W
Tafti
Mehdi
M
Franken
Paul
P
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D000077408:Modafinil; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010597:Pharmacogenetics; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012890:Sleep / Q000187:drug effects; D013045:Species Specificity; D013057:Spectrum Analysis; D013223:Statistics as Topic; D013997:Time Factors; D014851:Wakefulness / Q000187:drug effects* / Q000235:genetics*
D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; C470510:YKP10A; D010649:Phenylalanine; D000077408:Modafinil; D003913:Dextroamphetamine