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

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 B2 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.

Characterization of Pharmacological and Wake-Promoting Properties of the Dopaminergic Stimulant Sydnocarb in Rats

“…There was further increase in the magnitude and duration of theta activity produced by sydnocarb at 30 mg/kg that was well tolerated in the Irwin behavioral assay. These findings are consistent with the effect reported in the literature for D-AMPH (Young, 1988;Hasan et al, 2009) and the DATinhibiting agent methylphenidate (Hajós et al, 2008). Consistent with sydnocarb's molecular action at NET, selective NET inhibitors have also been reported to either induce or enhance theta activity (Hajós et al, 2003a).…”

In vitro characterisation of the novel positive allosteric modulators of the mGlu5 receptor, LSN2463359 and LSN2814617, and their effects on sleep architecture and operant responding in the rat

“…This is consistent with high levels of receptor occupancy that can be achieved with these compounds, compared to CDPPB and ADX47273, and high measured levels in the brain at in vivo active doses. The large magnitude of wakefulness observed with LSN2463359 and LSN2814617 is at least equal to that of other wake-promoting agents such as amphetamine and modafinil (Hasan et al, 2009) and the relative lack of substantial hyperactivity or rebound hypersomnolence suggests this wakefulness may be elicited via a different mechanistic pathway to that of psychostimulants. A small increase in wakefulness was previously reported with CDPPB dosed intraperitoneally at 30 mg/kg (ParmentierBatteur et al, 2012) which was not detected in the present study, although a wake-promoting effect of 300 mg/kg ADX47273 was observed.…”

Differential Effects of GABABReceptor Subtypes, γ-Hydroxybutyric Acid, and Baclofen on EEG Activity and Sleep Regulation

“…EEG and electromyogram (EMG) electrodes were implanted while the mice were under deep anesthesia as previously described (Hasan et al, 2009). Four to six days of recovery from surgery were allowed before connecting animals to the recording leads.…”