with increased levels of motivation and activity. At elevated levels DA appears to be involved with memory and learning [29], especially being involved with the association of various learned facts.
Norepinephrine (NE)
NE, also known as noradrenalin, maintains EEG activity, has reduced activity during NREM sleep, and has near complete loss of activity during REM. NE is most active in the wake state, is released by the LC, and is associated with an increase related to attention and activity that impacts the sympathetic nervous system [30]. NE may have an effect on orexin as it relates to arousal [23].
Serotonin (5HT)
5HT was initially known to be involved with sleep. At this time, it is known to modulate the sleep and the wake state, as well as the CR. This is associated with the area in the brain and the specific receptors that are impacted [31]. It is well known for a wide variety of functions associated with mood, depression, pain, and of course sleep. It is found to be excitatory and can impact the wake state. 5HT is most active during the wake state, less active in NREM, and has a low level of activity during REM [23].
Acetylcholine (ACH)
ACH is predominately for vigilance and cortical activation during the wake state and also in REM [32]. Found at the neuromuscular junction it is primarily involved with the parasympathetic nervous system. It is considered to have excitatory properties. It also plays a role in the precipitation of REM sleep, especially the phasic state and is critical for memory function [5].
Histamine (HA)
The main function of HA is to maintain calm wakefulness [33]. The role of HA was not known until it was recognized that antihistamines would produce sleepiness. Further investigation led to the discovery of the role of HA in the promotion of wakefulness and vigilance. It functions in a similar fashion to norepinephrine by promoting cortical activation during wakefulness. In people with narcolepsy or idiopathic hypersomnia there are low levels of HA [34]. A main source of HA in the brain is the tuberomammillary nucleus (TMN), close to the mammillary body [35]. Release of HA during NREM is minimal and there is none in REM.
Other Neurotransmitters of Arousal and Wakefulness
Orexin/Hypocretin
The origin is from the hypothalamus and the role of orexin (orexin A and B), also known as hypocretin (hypocretin 1 and 2), has been determined to be a neurochemical that maintains wakefulness [36]. These were discovered at about the same time, almost two decades ago, by two different research groups and hence the two different names. Its role is to maintain and stabilize wakefulness as well as vigilance. It is known to suppress REM and NREM sleep. A reduction in the presence of orexin is implicated in the presentation of narcolepsy. Consequently, specific medications that are designed to influence the release of orexin are used for the management of Narcolepsy and hence maintain wakefulness and vigilance. Orexin A levels have been shown to be lower in patients with OSA [37]. The orexin/hypocretin neurons are activated by glutamate [5].
Glutamate
This is an excitatory neurotransmitter that is associated with normal brain function and has a basic role in the activity of the waking brain. It is present mostly during wakefulness when the largest amounts can be found [38]. During NREM sleep, it declines but may spike with the onset of REM [24].
Cortisol
This substance (hormone) impacts arousal and wakefulness. Cortisol is released by the adrenal glands and is associated with stress. It plays a role in maintaining alertness and is increased in the early morning hours to promote wakefulness. Being increased with stress it may be associated with depression and insomnia. In patients with OSA cortisol release associated with awakening is reduced and with adequate management of the OSA the levels improve [39]. The release of cortisol is associated with the HPA axis (hypothalamic–pituitary–adrenal axis); however, this is somewhat controversial as it relates to sleep.
Neurotransmitters for Sleep
Neurotransmitters that promote sleep predominately originate from the hypothalamus.
GABA (Gamma‐Aminobutyric Acid or γ‐Aminobutyric Acid)
This is the main neurotransmitter of sleep and is released from the hypothalamus. Gamma‐aminobutyric acid (γ‐aminobutyric acid or GABA) inhibits activating systems with the greatest influence at the posterior hypothalamus hence promoting sleep [11]. Many of the more popular medications that are designed to promote sleep such as Ambien, Sonata, and Lunesta all promote the release of GABA. Benzodiazepine‐type medications also are known to increase GABA, which accounts for their sedating effects. GABA is synthesized from glutamate.
Adenosine
This is not a classic neurotransmitter. It may build up over time associated with ongoing activity and is a by‐product of degradation from adenosine triphosphate (ATP). The concentration of adenosine increases with prolonged wakefulness, increasing both the depth and duration of sleep, and decreases during sleep [40]. It is proposed that it may be a key neurotransmitter in the homeostatic regulation of sleep. It seems to have an inhibitory effect in the central nervous system on acetylcholine and glutamate. In addition, it has the role of facilitating sleep along with GABA. Its role in promoting sleep is exemplified by the fact that caffeine (methylxanthine) blocks adenosine receptors thus explaining the role of caffeine as a stimulant.
Glycine
This is an inhibitory neurotransmitter found in the spinal cord and inhibits motoneurons and thus is involved in the atonia associated with REM sleep.
Serotonin (5HT)
As previously discussed, the primary role of 5HT is in wakefulness, as well as the control of many different functions. There are many different receptors for 5HT and one specific group is involved in sleep. In this instance, 5HT is involved in NREM sleep; however, it is minimally present during REM sleep [31]. 5HT is derived from L‐tryptophan, an amino acid.
The Role of Melatonin
This is a hormone that is released by the pineal gland in the brain and its major impact is on the CR. Melatonin does not directly impact sleep like other neurotransmitters. The role of melatonin is to prepare areas of the brain for the action of neurotransmitters that promote sleep [41]. As such the release of melatonin is related to light. Light that penetrates the eye has an impact on the release of melatonin in a negative fashion. In the presence of light, the release of melatonin is turned off. As darkness approaches the absence of light, penetrating the eye is the stimulus to release melatonin thus promoting sleep.
The pathway that impacts the release of melatonin is not a direct one. The absence of light triggers neural activity that proceeds from the suprachiasmatic nucleus (SCN) in the brain stem to the hypothalamus. The signal proceeds to the superior cervical nucleus of the spinal column and then to the pineal gland (Figure 2.5).
Flip‐Flop Switch
The neurotransmitters involved in the sleep–wake cycle interact such that they have an effect on one other, referred to as the flip‐flop switch. This is viewed as a balance between the wake promoting and sleep promoting neurotransmitters. In this model, there is a trigger that causes a switch in states between sleep and wakefulness to occur [42].
The Circadian Rhythm
Our CR or cycle is directly related