Sleep and Its Modulation by Substances That Affect GABAA Receptor Function

Abstract

The GABAA receptor is the target of various endogenous and synthetic substances modulating sleep–wake behavior. According to its physiological role, the GABAA receptor mediates not only the effects of sleep-promoting substances but also of the whole range of agonists, partial agonists, antagonists, partial inverse agonists, and inverse agonists, resulting in a wide spread spectrum of the effects on sleep ranging from sleep promotion to sleep inhibition. Synthetic agonists at the GABAA receptor include barbiturates, which are obsolete today, the classical benzodiazepines and the so-called nonbenzodiazepine hypnotics. Generally, these substances help to enter and to maintain sleep. Their effects on sleep architecture and microstructure of sleep are opposite to those of sleep promotion after sleep deprivation as these agonists suppress slow wave sleep, rapid-eye-movement (REM) sleep, and electroencephalogram (EEG) power in the lower frequency bands, whereas they enhance EEG power in the higher frequency bands. In contrast, the selective extrasynaptic GABAA receptor agonist gaboxadol and the GABA-uptake inhibitor tiagabine mimic the effects of sleep deprivation. The synthetic partial agonist bretazenil shares some of the sleep-EEG effects of benzodiazepines. The synthetic antagonist flumazenil exerts some effects on sleep EEG, suggesting that the substance has its own intrinsic effects or acts as an antagonist to an endogenous ligand. A few previous studies report inverse agonistic effects of β-carbolines on sleep-EEG recordings. Furthermore, certain neuroactive steroids (pregnenolone, THDOC, progesterone, allopregnanolone, dehydroepiandrosterone) and neuropeptides (growth hormone-releasing hormone, neuropeptide Y, and galanin) exert specific effects on sleep EEG, which may be mediated by the GABAA receptor. This chapter aims to review the state of the art in this field.