Sleep circuitry and the hypnotic mechanism of GABAA drugs.

Early in the twentieth century, von Economo provided the first evidence linking the hypothalamus with sleep-wake behavior. His studies concluded that the anterior hypothalamus was associated with sleep, whereas the posterior hypothalamus was associated with waking. In the decades following these observations, a wealth of research has shown that an elaborate circuitry comprising a number of brain regions, cell types, and extracellular messengers underlies sleep-wake behavior. In this review, we discuss data generated in the past 10 years that highlight the role of the hypothalamus in sleep-wake behavior and control. In particular, we will focus on the identification of the ventrolateral preoptic nucleus (VLPO) as a sleep center and the hypocretin/orexin cells in the perifornical region of the hypothalamus as constituting a waking center; these two centers are critical for the maintenance of normal sleep-wake architecture, and provide a foundation for our understanding of sleep-wake behavior and its underlying physiology. The data from these and other regions traditionally associated with the sleep-wake cycle have led to a flip-flop switch model of sleep-wake control. The switch is composed of two sets of mutually inhibitory groups of neurons: a sleep group and an arousal group, with the latter modulated by orexin-containing neurons in the lateral hypothalamus. The sleep-promoting GABA (gamma-amino-butyric acid) receptor agonists are a diverse class of drugs, which include barbiturates, benzodiazepines, chloral hydrate, ethanol, and gaseous anesthetics, that have been used to study sleep physiology for many years. Recent studies suggest that these drugs may exert their hypnotic effects in a regionally specific manner. For example, some GABAA agonists appear to promote sleep by inhibiting the histaminergic cells in the tuberomammillary nucleus and weakly activating the VLPO via agonist binding to the alpha1 subunit of GABAA receptors; whereas, gaboxadol (THIP; 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) binds to the alpha4delta-subunits, potentially promoting sleep by activation of the VLPO. The integration of these data into the flip-flop switch model can be used to better understand sleep-wake control and augment existing therapeutic treatments for sleep disorders.