Neuronal Networks Regulating Sleep and Arousal: Effect of Drugs

The three vigilance states (wakefulness [W], slow wave sleep [SWS], rapid eye movement sleep [REMS]) are controlled by distinct, but interconnected, networks of neurons. The sleep/arousal network consists of separate systems of W-promoting and SWS-promoting neurons, located in nuclei in the basal forebrain, diencephalon and brainstem. Each neuronal system operates via a distinct neurotransmitter, providing its unique “neurochemical signature”. W-promoting neurons are active during W and quiescent during SWS, whereas SWS-promoting neurons are active during SWS and cease to fire during W. The level of arousal at any one time reflects the intricate balance between W-promoting and SWS-promoting systems. W is the result of cortical activation by W-promoting neurons; sleep ensues when SWS-promoting neurons switch off the W-promoting systems. REMS is regulated by a network of REMS-promoting and REMS-inhibiting neurons located in the brainstem and hypothalamus. A third network is responsible for the regulation of the circadian rhythmicity of the wakefulness/sleep cycle. The neurochemical signatures of W-promoting and SWS-promoting neurons make it possible to develop drugs that, by targeting specific neuroreceptors and synaptic mechanisms, have predictable effects on sleep and arousal. Arousal-modifying drugs act by tipping the balance between W-promoting and SWS-promoting neuronal activity. Thus a sedative drug, useful for the treatment of insomnia, may act by activating a SWS-promoting system (e.g. benzodiazepines, melatonin receptor agonists) or inhibiting a W-promoting system (e.g. H1-antihistamines, orexin receptor antagonists). Conversely, an alerting drug, useful for the treatment of excessive daytime sleepiness, may inhibit a SWS-promoting system or activate a W-promoting system (e.g. psychostimulants, H3 histamine receptor antagonists).