Benzodiazepines are allosteric modulators of GABA-A receptors which increase inhibition in neuronal networks. They have a broad spectrum of applications in clinical medicine including sedation, treatment of anxiety, and anticonvulsive therapy. In accordance with this mechanism of action, benzodiazepines have been reported to slow the frequency of network oscillations in rodents. However, a detailed analysis of the effects of benzodiazepines on different cortical oscillations is lacking. Moreover, recent evidence indicates that the interaction between different simultaneous network oscillations (cross frequency coupling) is of special importance for cognitive tasks including working memory and behavioural choice. We have therefore measured the effect of diazepam on slow and fast network oscillations in mouse neocortex, including the cross-frequency coupling between theta (4–12 Hz), gamma (40–100 Hz) and fast gamma (120–160 Hz) oscillations. We performed field potential (EEG) recordings in freely moving mice during the light period, 30 minutes after systemic injections of drugs (vehicle: cyclodextrin, diazepam: 1mg/kg, 2mg/kg or 4mg/kg, i.p.). The following behavioural / vigilance states were differentiated: active waking, quiet waking, NREM sleep, tonic REM and phasic REM sleep.

Our findings confirm the slowing of low frequency oscillations by diazepam. In addition, we found state-specific changes of high frequency oscillations, and a decrease in strength of cross-frequency coupling between theta-phase and high frequency oscillations (gamma and fast gamma). The effects were dose-dependent. Our findings may hint towards a specific effect of benzodiazepines on neuronal oscillations which are important for task performance, cognition and memory.