The part of the brain most important in regulating sleep duration is the hypothalamus. Certain groups of hypothalamic neurons and adjacent groups of basal forebrain neurons produce the neurotransmitterγ-aminobutyric acid (GABA). Projections of these GABA neurons inhibit the firing of cells involved in wakefulness. Several groups of neurons have been shown to be inhibited, including neurons containing histamine, norepinephrine, serotonin, hypocretin, and glutamate—and this inhibition promotes sleep. (Siegel, 2004) Other neurotransmitters are gamma-aminobutyric acid, orexin, melanin-concentrating hormone, cholinergic, galanin, noradrenaline, and histamine. Nutritional interventions that may act on these neurotransmitters in the brain may also sleep. Carbohydrate, tryptophan, valerian, melatonin, and other nutritional interventions have been investigated as possible sleep inducers and represent promising potential interventions. (Halson, 2014)
Research on the neural mechanisms involved in sleep-wake regulation suggests that the sleep-wake state is controlled by a complex interaction between wakefulness-promoting and sleep-promoting nuclei in the hypothalamus and brainstem. Wake-promoting neurons include orexinergic and histaminergic nuclei in the hypothalamus, cholinergic nuclei in the brainstem, adrenergic nuclei in the locus coeruleus, serotonergic nuclei in the raphe nuclei, and dopaminergic nuclei in the midbrain ventral tegmental area. Sleep is promoted by nuclei in the basal forebrain, ventrolateral preoptic area, and anterior hypothalamus through the inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and galanin. Adenosine, which has been proposed to be involved in the homeostatic regulation of sleep, may promote sleep through anticholinergic activity in the basal forebrain and brainstem. Drugs with pharmacologic effects at receptors involved in sleep-wake regulation may therefore have effects on sleep-wake behavior. These effects may be therapeutic (e.g., improve sleep or enhance wakefulness) or impairing (e.g., cause sleep disturbance or daytime sedation). (Schweitzer, 2017)
GABA/GLUTAMATE
Recently, accumulating evidence indicates that the backbone of the sleep−wake regulatory system mainly depends on the fast neurotransmitters, especially glutamate and γaminobutyric acid (GABA). (He, 2019)
NOREPINEPHRINE
The neurotransmitter norepinephrine (NE), through its involvement in the ascending arousal system, impacts the efficacy of many wake- and sleep-promoting medications. (Mitchell, 2010)
HYPOCRETIN/OREXIN
The orexin peptides are produced only by a cluster of neurons in the lateral hypothalamus but are released by projections of these neurons to the CNS, from the cortex to the spinal cord. The orexin neurons heavily innervate several regions that promote arousal and suppress REM sleep, including the basal forebrain, tuberomammillary nucleus (TMN), periaqueductal grey (PAG), dorsal raphe (DR), and locus coeruleus (LC). (Mahoney, 2019) The orexin neurons are characterized by their wake-promoting system. (Ferreira et al, 2017) The orexin (hypocretin) system regulates sleep and wakefulness through interactions with systems that regulate emotion, reward, and energy homeostasis. (Sakurai , 2007)
Cortical electroencephalographic activity arises from corticothalamocortical interactions, modulated by wake-promoting monoaminergic and cholinergic input. These wake-promoting systems are regulated by hypothalamic hypocretin/orexins. (Schwartz , 2015)
SEROTONIN
Serotonergic activity may be accompanied by waking or sleep depending on the brain area and receptor type involved in the response. (Ursin, 2002) It is currently accepted that serotonin (5-HT) functions predominantly to promote wakefulness (W) and to inhibit REM (rapid eye movement) sleep (REMS), yet, under certain circumstances, the neurotransmitter contributes to the increase in sleep propensity. (Monti, 2011)
CORTISOL
A hormone that promotes wakefulness and alertness. Usually higher in the morning.
DOPAMINE
Maintains wakefulness, but also is involved with REM sleep. A reduction is associated with a movement disorder.
ADENOSINE
Facilitates sleep. It is inhibited by caffeine.
MELANIN
The melanin-concentrating hormone (MCH) is an essential neuromodulator involved with homeostatic regulation and motivated behaviors. MCH system has been identified as a sleep-promoting system. (Ferreira et al, 2017) Melatonin and related compounds increase sleep by suppressing the activity of the neurons in the brain's circadian clock, and NE influences the synthesis of melatonin. (Mitchell, 2010)
Melatonin is a key marker of circadian function. Melatonin is secreted by the pineal gland and levels peak in the middle of the night. Light suppresses the normally observed nocturnal rise in melatonin. Melatonin can be measured in the blood, saliva, and urine, and both the timing and amplitude of secretion can be evaluated as measures of circadian alignment. (Abbott, 2017)
HISTAMINE
Activity in histamine neurons is essential for normal wakefulness, especially at specific circadian phases, and reducing activity in these neurons can produce sedation. Antihistamines block the wake-promoting effects of histamine, which shares reciprocal signaling with NE. (Mitchell, 2010)
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Sabra M. Abbott, Roneil G. Malkani, Phyllis C. Zee, Chapter 39 - Circadian Dysregulation in Mental and Physical Health, Editor(s): Meir Kryger, Thomas Roth, William C. Dement, Principles and Practice of Sleep Medicine (Sixth Edition), Elsevier, 2017.
Paula K. Schweitzer, Angela C. Randazzo, Chapter 45 - Drugs that Disturb Sleep and Wakefulness, Editor(s): Meir Kryger, Thomas Roth, William C. Dement, Principles and Practice of Sleep Medicine (Sixth Edition), Elsevier, 2017.