Wake-promoting system

During the last decade, research lent support to the idea that three interacting neuronal systems (a wake-promoting system, a NREM-promoting system and a REM-... 

Disturbances of the wake-promoting system the hyperarousal theory of depression... 

A medication that causes induction of sleep. The majority of currently available hypnotics (for example benzodiazepine receptor agonists) act via potentiating the brain s inhibitory GABAergic systems, in turn reducing the activity of arousal (i.e. wake promoting) neurotransmitter systems. 

Some CNS stimulants have an effect on the same systems that are involved in wakefulness, including glutamate-, NE-, DA-, 5-HT-, histamine-, hypocretin- and ACh-containing neurons. This group includes molecules such as cocaine, amphetamine, and nicotine. The sleep-promoting systems are concentrated in the medial part of the brainstem, dorsal reticular substance of the medulla, anterior hypothalamus, and basal forebrain (Jones 2005). Other stimulants, such as caffeine and theophylline, block some sleep-inducing mechanisms. Modafinil is also a CNS stimulant with an unknown mechanism of action. 

To summarize, there is now strong evidence that sleep disturbances encountered in major depression are associated with an increase of wake-promoting mechanisms linked to a stress-related hyperarousal reaction implicating the CRH and the LC-AN systems. 

Pathological conditions in which the VLPO system is weakened (i.e. less drive for sleep) could, therefore, result in more frequent changes between wakefulness and sleep, as has been demonstrated in animal models. Interestingly, elderly individuals have significantly reduced numbers - often by as much as 50% - of sleep-promoting VLPO neurones, an age-related loss of VLPO cells that may explain, at least partially, this population s characteristic difficulty in falling and staying asleep. 

Complicated processes govern wakefulness, sleep, and the transitions leading to sleep initiation and maintenance. Although the neurophysiology of sleep is complex, certain neurotransmitters promote sleep and wakefulness in different areas of the central nervous system (CNS). Serotonin is thought to control non-REM sleep, whereas cholinergic and adrenergic transmitters mediate REM sleep. Dopamine, norepinephrine, hypocretin, substance P, and histamine all play a role in wakefulness. Perturbations of various neurotransmitters are responsible for some sleep disorders and explain why various treatment modalities are beneficial. 

Some arousal-related neurotransmitters, including noradrenaline, serotonin, and acetylcholine, feed back to inhibit POA sleep-active neurons. This aspect of the system has been reviewed previously (McGinty Szymusiak, 2000 Saper et al., 2001). Therefore, once sleep-active neurons are activated, arousal-related neurons are inhibited, and inhibitory control of sleep-active neurons by arousal systems is reduced. In this way, sleep onset is facilitated. That is, the mutually inhibitory systems can switch more quickly from wake to sleep, and back. These mutually inhibitory interactions also promote stability of both waking and sleep. 

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