Abstract
GABA-ergic neurotransmission plays a key role in sleep regulatory mechanisms and in brain oscillations during sleep. Benzodiazepines such as diazepam are known to induce sedation and promote sleep, however, EEG spectral power in slow frequencies is typically reduced after the administration of benzodiazepines or similar compounds. EEG slow waves arise from a synchronous alternation between periods of cortical network activity (ON) and silence (OFF), and represent a sensitive marker of preceding sleep-wake history. Yet it remains unclear how benzodiazepines act on cortical neural activity during sleep. To address this, we obtained chronic recordings of local field potentials and multiunit activity (MUA) from deep cortical layers of the primary motor cortex in freely behaving mice after diazepam injection. We found that the amplitude of individual LFP slow waves was significantly reduced after diazepam injection and was accompanied by a lower incidence and duration of the corresponding neuronal OFF periods. Further investigation suggested that this is due to a disruption in the synchronisation of cortical neurons. Our data suggest that the state of global sleep and local cortical synchrony can be dissociated, and that the brain state induced by benzodiazepines is qualitatively different from spontaneous physiological sleep.
Highlights
Benzodiazepines are frequently prescribed as sedatives, anxiolytics and anticonvulsants, with 5.2% US adults aged 18–80 reported to be using benzodiazepines in 2008 [53]
Post hoc paired ttests revealed a significant increase in the total amount of both non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep over the 24 h post injection after diazepam injection as compared to vehicle (NREM sleep: vehicle 10.33 ± 0.34 h, diazepam 11.19 ± 0.34 h, p = 0.03; REM sleep: vehicle 1.32 ± 0.05 h, diazepam 1.58 ± 0.10 h, p = 0.03)
There was a redis tribution of REM episode durations, with fewer longer lasting REM sleep episodes occurring after diazepam injection (Repeated measures ANOVA (Greenhouse-Geisser); Time: F(2.8, 38.1) = 308.68, p < 0.0001; Injection condition: F(1,14) = 3.36, p = 0.09; Interaction: F(2.7, 38.1) =
Summary
Benzodiazepines are frequently prescribed as sedatives, anxiolytics and anticonvulsants, with 5.2% US adults aged 18–80 reported to be using benzodiazepines in 2008 [53]. Benzodiazepines are highly addictive, and patients taking them on a regular basis develop tolerance and prominent with drawal symptoms, which can lead to their misuse [48], while chronic use is often ineffective or can lead to impairments in cognition [5,30,62]. For these reasons, benzodiazepines and other hypnotic drugs are not generally recommended for the treatment of insomnia and should be limited to short-term use [61,63,64,68]. Benzodiazepines remain a prevalent treatment for sleep disruptions, with pharmacological interventions resulting in similar short-term treatment outcomes for persistent insomnia as compared to behav ioural interventions [74], and even low doses reported to produce sig nificant hypnotic effects [72]
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