SEROTONIN: ROLE IN

SLEEP ONSET

A PRESENTATION BY: NWANI CHIDERA MERCY

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INTRODUCTION TO TERMS
• SEROTONIN: Serotonin, or 5-hydroxytryptamine (5-HT), is an
indolamine neurotransmitter that regulates various activities, including
behaviour, mood, and memory. It is synthesized in the raphe nuclei of
the brainstem and the enterochromaffin cells of the intestinal mucosa
(Bamalan & Al Khalili, 2020).
• SEROTONERGIC PATHWAY:

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INTRODUCTION TO TERMS
• SLEEP: Sleep, a physiological process, is characterized by a reversible
unconscious state, reduced body temperature, blood pressure, and
breathing rate (Rama et al.., 2013).
• SLEEP ONSET: The moment in time when the EEG pattern changes
from wakefulness to sleep; operational definitions of sleep onset vary.
The shift from consciousness to sleep is referred to as sleep onset
(Keenan et al.., 2013).

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HISTORY OF SEROTONIN
• Vittorio Erspamer, a Roman chemist, found the
chemical serotonin for the first time in 1935
(Kitson, 2007; Bakshi & Tadi, 2020).
• Maurice M. Rapport, Arda Green, and Irvine
Page of the Cleveland Clinic isolated and
identified serotonin in 1948.
• Rapport because of its structure proposed the
hormone be called 5-hydroxytryptamine
(Nichols & Nichols, 2008).

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SEROTONIN
• Serotonin, or 5-hydroxytryptamine (5-HT), is an indolamine
neurotransmitter wwhich regulates various activities, including
behaviour, mood, memory, and gastrointestinal homeostasis.
• It is synthesized from tryptophan in the raphe nuclei of the brainstem
and the enterochromaffin cells of the intestinal mucosa (Bamalan & Al
Khalili, 2020).
• The synthesis of serotonin (5-HT) begins with the hydrolyzation of
essential amino acid tryptophan to produce 5-hydroxy-L-tryptophan
(5-HTP) and decarboxylation to produce 5-hydroxytryptamine (5-HT)
(Bamalan & Al Khalili, 2020).

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SEROTONIN
● The serotonergic system originates from the raphe nuclei in the
brainstem and extends throughout the central nervous system
(Hornung, 2003).

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SEROTONIN RECEPTORS
● The activation of distinct types of serotonin receptors further
modulates the effects of serotonin pathways (Celada et al., 2013).
● Serotonin receptors are a G protein-coupled receptors and ligand-
gated ion channels that bind to serotonin.
● They are classified into seven main subtypes: 5-HT1A, 5-HT1B,
5-HT1D, 5-HT1E, 5-HT2A, 5-HT2B, and 5-HT2C. The activation
of these receptors has different excitatory and inhibitory effects on
the serotonergic pathway, depending on the subtype and the
location of the receptor (Pithadia, 2009).
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SEROTONIN AND THE SLEEP-WAKE
CYCLE
● The sleep/wake cycles are triggered by chemicals in the brain
called neurotransmitters. These include norepinephrine, histamine,
and serotonin (Scammell, 2015).
● Serotonin plays a definite role in sleep cycles i.e. onset maintenance
and termination, as high levels of serotonin are associated with
wakefulness and lower levels with sleep (Oikonomou et al., 2019).
● The effect of the serotonergic pathway on sleep onset depends on
factors such as location, activity, and receptor especially 5-HT1A &
5-HT2 receptors (Vaseghi et al., 2021; Deka et al., 2020).
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5-HT1A & 5-HT1B RECEPTORS
● The 5-HT1A and 5-HT1B receptors play a crucial role in regulating
sleep and wakefulness through various presynaptic and
postsynaptic actions.
● They produce an inhibitory feed back to serotonergic raphe
neurons, with studies suggesting that stimulation of 5-HT1A
receptors by systemic administration of agonists increases
wakefulness and decreases sleep (Portas & Janne Grønli, 2008).

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5-HT1A & 5-HT1B RECEPTORS
● Local administration of agonists in the dorsal raphe nucleus decreases
wakefulness and increases REM sleep via inhibition of mesopontine
REM sleep promoting neurons. Systemic administration of 5-HT1B and
5-HT 1B receptor agonists increases wakefulness and decreases REM
sleep.
● The role of these receptors in modulating circadian rhythm is important
and they affect the response of the suprachiasmatic nucleus to light and
the secretion of melatonin from the pineal gland (Portas & Janne Grønli,
2008).

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5-HT2A receptors
● The 5-HT2A receptor is distributed in brain regions involved in waking
states (Dorsal and Medial Raphe Nuclei), Non-REM sleep states (medial
and lateral preoptic area, anterior and lateral hypothalamic areas,
nonspecific thalamic nuclei), and REM sleep states.
● They have also been characterized in the cerebral cortex, limbic system,
and basal ganglia (Monti et al., 2018).
● The activation of 5-HT2A receptors by agonists enhance wakefulness and
suppress slow wave sleep (SWS). and REM sleep (Vanover & Davis, 2010).

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5-HT6 receptors
● Mainly expressed in the striatum, hippocampus, and cerebellum
● Modulates release of glutamate, GABA, and dopamine in these
brain regions
● Increases wakefulness and reduces slow wave sleep and rapid eye
movement sleep
● Implicated in learning, memory, and motor coordination

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5-HT7 RECEPTORS
● These receptors are predominantly found in the thalamus, the
hypothalamus, and the cortex (HEDLUND & SUTCLIFFE, 2004).
● They regulate the release of acetylcholine, histamine, and orexin in
these brain areas. 5-HT7 receptors are also involved in
thermoregulation, circadian rhythms, and mood.
● Activation of 5-HT7 receptors enhances wakefulness and inhibits
SWS and REM sleep (Monti, 2013).

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SEROTONIN & SLEEP
• The effect of the serotonergic pathway on sleep onset is determined by
the balance between the activation of 5-HT1A and 5-HT2 receptors
(Monti & Jantos, 1992; Vanover & Davis, 2010).
• This balance can be influenced by several factors, such as the
circadian rhythm, the sleep-wake cycle, and pharmacological agents.
For example, during the day, when wakefulness is favoured, there is a
higher activity of the SCN and orexin neurons, which stimulate the
DRN and increase its release of serotonin (Muraki, 2004)..

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SEROTONIN & SLEEP contd.
• This activates both 5-HT1A and 5-HT2 receptors, but the net effect is
an increase in arousal due to the dominance of 5-HT2 receptors.
• During the night, when sleep onset is favoured, there is a lower
activity of the SCN and orexin neurons, which inhibit the DRN and
decrease its release of serotonin. This activates mainly 5-HT1A
receptors, which inhibit both the serotonin neurons and their target
neurons. This results in a decrease in arousal and an increase in sleep
onset.

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SEROTONIN, SLEEP & THE DORSAL
RAPHE NUCLEUS (DRN).
•The raphe nuclei synthesize the majority of serotonin in the central
nervous system (Walker & Tadi, 2020).
•The dorsal raphe nucleus (DRN). is a brain region that contains
different types of neurons, such as serotonin (5-HT), dopamine, GABA,
and glutamate neurons. It is involved in the regulation of sleep and
wakefulness, especially the rapid eye movement (REM). sleep phase.
•DRN 5-HT neurons are active during wakefulness and inhibit REM
sleep. They also modulate the activity of other brain regions that control
sleep and arousal, such as the hypothalamus and the thalamus (Cai et al.,
2022).
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ESSENTIAL BRAIN REGIONS FOR
SLEEP
• Ventrolateral preoptic nucleus (VLPO).
• Pineal Gland
• Reticular Activating System (RAS).
• Suprachiasmatic nucleus (SCN). (Falup‑Pecurariu et al., 2021).

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SEROTONIN & THE VENTROLATERAL
PREOPTIC AREA (VLPO).
• In the ventrolateral preoptic nucleus (VLPO), the main structure that
triggers non-rapid eye movement (NREM). sleep, putative sleep-
promoting (PSP). neurons were shown to be either inhibited (Type-1).
or excited (Type-2). by 5-HT application.
• 5-HT receptors are differentially expressed in Type-1 and Type-2
neurons. Type-1 neurons express 5-HT1A receptors, which mediate
the inhibitory effect of 5-HT. Type-2 neurons express 5-HT 2C
receptors, which mediate the excitatory effect of 5-HT

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SEROTONIN & THE VENTROLATERAL
PREOPTIC AREA (VLPO).
• Type-1 neurons are inhibited by serotonin through the activation of 5-
HT 1A receptors. These receptors reduce the firing and the release of
serotonin from the serotonergic neurons. This leads to a decrease in
arousal and an increase in sleep onset (Sangare et al., 2016; Vaseghi et
al., 2021).

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SEROTONIN & THE ASCENDING
RETICULAR ACTIVATING SYSTEM
• The ascending reticular activating system (ARAS). is a set of connected nuclei in
the brainstem that is responsible for regulating wakefulness and sleep-wake
transitions (Iwańczuk & Guźniczak, 2015; Brudzynski, 2013).

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SEROTONIN AND THE PINEAL GLAND
(SYNTHESIS OF MELATONIN).

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CLINICAL IMPLICATIONS OF
SEROTONIN’S ROLE IN SLEEP ONSET
• Sleep and depression are highly associated. The most common
disturbances in the sleep pattern of a depressed person are low sleep
efficiency and little deep sleep. Poor sleep has been shown to be a risk
factor for the development or recurrence of depression.
• Selective serotonin reuptake inhibitor (SSRI). use is consistently
associated with good subjective sleep in clinically depressed patient
populations However, studies in the general population are lacking
(Aarts et al., 2016).

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 THANK YOU

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