Role of GABAA receptors in the regulation of sleep: initial sleep responses to peripherally administered modulators and agonists.

This paper reviews the sleep effects of systemically administered agonistic modulators of GABAA receptors, including barbiturates, benzodiazepines, zolpidem, zopiclone and neuroactive steroids, and the selective GABAA agonists muscimol and THIP. To assess the involvement of GABAA receptors in the physiologic regulation of sleep, the article emphasizes the hypnotic properties shared by agonistic modulators and by the selective agonists of the GABAA receptor complex. In both rats and normal sleeping individuals, agonistic modulators are able to reduce sleep latency, increase sleep continuity, and promote non-rapid-eye-movement (NREM) sleep as well as the occurrence of spindles. Furthermore, nearly all of these compounds have been shown to attenuate slow-wave activity (SWA) and to suppress the occurrence of REM sleep. In the same species, GABAA agonist(s) do not seem to affect sleep latency or REM sleep time, but may increase sleep continuity and NREM sleep and augment SWA while depressing spindle activity in humans. The distinct sleep effects of GABAA agonists may be due to their unspecific stimulation of GABAA receptors throughout the brain, and to the fact that they are poor substrates for uptake and probably exert more tonic effects than liberated GABA. If so, the involvement of GABAA receptors in the various aspects of sleep can be inferred more accurately from the hypnotic effects of agonistic modulators. This implies that an activation of GABAA receptors plays a crucial role in the initiation and maintenance of NREM sleep and in the generation of sleep spindles, but disrupts the processes underlying slow EEG components and the triggering of REM sleep.