Elsevier

Sleep Medicine

Volume 49, September 2018, Pages 31-39
Sleep Medicine

Original Article
Serotonin: its place today in sleep preparation, triggering or maintenance

https://doi.org/10.1016/j.sleep.2018.05.034Get rights and content

Highlights

  • Axonal 5-HT release, waking state-dependent, favors synthesis of hypnogenic substances.

  • Dendritic 5-HT release, sleep states-dependent, contributes to 5-HT neurons silencing.

  • Nitric oxide, co-synthesized with 5-HT, may act in synergy with it.

  • Hypnogenic substances act on 5-HT and substance P components of the n. raphe dorsalis.

  • Serotonin is involved in sleep preparation, triggering and maintenance.

Abstract

Serotonin (5-HT) is involved in sleep in two different ways. First, when released during waking by the axonal nerve endings, it influences the synthesis of hypnogenic substances in specific brain targets. Such a synthesis might be in keeping with the waking qualitative aspects. As an example, the hypnogenic CLIP peptide (ACTH18-39) is synthesized when stressful events occur during wakefulness. Second, when released during sleep within the nucleus raphe dorsalis (nRD) by dendrites of 5-HT neurons, it contributes to 5-HT perikarya silencing through an auto-inhibitory process. Nitric oxide, co-synthesized with 5-HT, may act in synergy with this amine at both mentioned levels. Regarding the triggered hypnogenic substances, they induce sleep through acting on two components within the nRD: (1) the 5-HT component; its silencing is necessary to remove the gating effect exerted on phasic sleep events (ponto-geniculo-occipital, PGO, waves); (2) a substance P component; its silencing is necessary, at least, to alleviate the tonic influence exerted on somatic muscles. These two components may constitute the brain “sleep switch-on” mechanism allowing wake/sleep alternation. Pharmacological procedures influencing this switch may be determinant for treating insomniac patients. Serotonin appears thus to be involved in sleep preparation, triggering and maintenance.

Section snippets

First implication of serotonin in the sleep field

Serotonin or 5-hydroxytryptamine (5-HT) entered the sleep field by way of the seminal work of Brodie and coworkers in 1955 suggesting that reserpine was able to produce a depletion of serotonin together with sedation or a “sleep like state” [1]. Although such an approach faced a mountain of unknowns, for the first time, it formulated a possible link between serotonin and sleep and attracted the attention of hypnologists. The topography of brain monoamines, notably that of serotonin-containing

Brain anatomical substrate for serotonin

When the study of the brain substrate for serotonin began, only acetylcholine was considered as a true central neurotransmitter, its topography being known by way of cholinesterase histochemistry. In 1964, Dahlström and Fuxe [8] determined the first brain localization of serotonin-containing neurons using histofluorescence [9]. This was a real revolution in the study of monoamines in the central nervous system (CNS). Besides the technique of histofluorescence, immunohistochemical methods using

Electrolytic lesion of the raphe nuclei

Since the 5-HT component of the raphe system exhibits a limited dispersion, it was quite easy to achieve its electrolytic destruction. When the lesion of the rostral part of this system (ponto-mesencephalic subdivision) was achieved in the cat, a significant insomnia took place (duration 10–15 days) [11]. It was then possible to establish correlations between the insomnia intensity, the volume of the lesion achieved and the telencephalic 5-HT concentration that remained 10 days after lesion.

Cooling of the nucleus raphe dorsalis induces SWS and PS in the cat

In the “semi-chronic” animal preparation (head restrained; brachial plexuses cut; spinal cord transected at T4; constant infusion of procaïne at the surgical sites; patenteral feeding) [18], [19] all states of sleep (SWS and PS) occurred spontaneously after surgical recovery. Moreover, in light of the 5-HT sleep theory, localized moderate cooling (+10 °C) of the nRD, an area containing the great majority of the 5-HT perikarya, was expected to induce wakefulness, since its cooling could block

Detection of 5-OHle compounds during the sleep-wake states in the nRD

In the nRD, a structure rich in 5-HT cell bodies and dendrites [10], the 5-OHle signal exhibits variations opposite to those observed in the areas receiving 5-HT axonal nerve endings, ie, an increase during SWS and PS, compared to the waking state (Fig. 4b, c) [27], [28], [31], [32], [33]. Such variations take place particularly within the nRD clusters of serotoninergic perikarya located in the anterior part of the nucleus. They could reflect the existence of a dendritic 5-HT release occurring

Conclusions

According to the data reported and discussed here it appears that serotonin could be involved in sleep processes in two different ways: (1) when released by the axonal nerve endings during the waking state, it influences the synthesis of hypnogenic substances in specific brain targets; (2) when released by dendrites under the triggering influence of hypnogenic substances, it then contributes to the silencing of the 5-HT perikarya through an auto-inhibitory process. It is likely that NO,

Funding sources

Writing of this chapter did not receive any specific grant from funding agencies in the public, commercial, or profit sectors.

Acknowledgements

I would like to thank Pr. Michel Jouvet for his constant help regarding the research conducted on the role played by serotonin in sleep. This research started when serotonin was suggested to be the brain somnotonin. However, the first experiments that I performed in using brain localized cooling were not in favor of such a role. After 30 years of research, it appears that serotonin is involved in sleep in a complex way that concerns sleep preparation, triggering and maintenance. I am also

References (49)

  • M. Sallanon et al.

    Serotoninergic mechanisms and sleep rebound

    Brain Res

    (1983)
  • F. Houdouin et al.

    Effects induced by the electrical stimulation of the nucleus raphe dorsalis upon hypothalamic release of 5-hydroxyindole compounds and sleep parameters in the rat

    Brain Res

    (1991)
  • F. Riou et al.

    Endogenous peptides and sleep in the rat. III: the hypnogenic properties of vasoactive intestinal polypeptide

    Neuropeptides

    (1982)
  • B. Elkafi et al.

    Is the nucleus raphe dorsalis a target for the peptides possessing hypnogenic properties?

    Brain Res

    (1994)
  • B. Elkafi et al.

    Sleep permissive components within the dorsal raphe nucleus in the rat

    Brain Res

    (1995)
  • B. Bjorvatn et al.

    Sleep/waking effects of a selective 5-HT receptor agonist given 1A systemically as well as perfused in the dorsal raphe nucleus in rats

    Brain Res

    (1997)
  • J.M. Monti et al.

    Increased REM sleep after intra-dorsal raphe nucleus injection of flesinoxan or 8-OHDPAT: prevention with WAY 100635

    Eur Neuropsychopharmacol

    (2002)
  • B.B. Brodie et al.

    Evidence that serotonin has a role in brain function

    Science

    (1955)
  • A.B. Rothballer

    The effect of phenylephrine, methamphetamine, cocaine, and serotonin upon the adrenaline-sensitive component of the reticular activating system

    Electroencephalogr Clin Neurophysiol

    (1957)
  • P.B. Bradley

    The effects of 5-hydroxytryptamine on the electrical activity of the brain and on behaviour in the conscious cat

  • W.P. Koella et al.

    Mechanism of the EEG synchronizing action of serotonin

    Am J Physiol

    (1966)
  • J. Magnes et al.

    Synchronization of the EEG produced by low-frequency electrical stimulation of the region of solitary tract

    Arch Ital Biol

    (1961)
  • J.D. Bronzino

    Verification of neural pathway between reticular formation and the nucleus tractus solitarius

    Proc Eighth Int Conf Med Biol Eng

    (1969)
  • A. Dahlström et al.

    Localization of monoamines in the lower brain stem

    Experientia

    (1964)
  • Cited by (32)

    • Comprehensive quantitative method for neurotransmitters to study the activity of a sedative-hypnotic candidate using microdialysis and LC×LC-MS/MS

      2022, Talanta
      Citation Excerpt :

      Several common and vital metabolites closely linked to sleep NTs, such as glutamate, serotonin, norepinephrine, adenosine, acetylcholine, histamine, and taurine, were simultaneously analyzed. Glutamate is the most important excitatory neurotransmitter in the central nervous system [14], and serotonin is thought to be related to the preparation, triggering, and maintenance of sleep [15]; adenosine is one of the strongest endogenous sleep-promoting factors [16]. Additionally, the concentrations of NTs in five different regions of the brain associated with sleep were analyzed by microdialysis and LC-MS/MS.

    • Nicotinamide mononucleotide (NMN) and NMN-rich product supplementation alleviate p-chlorophenylalanine-induced sleep disorders

      2022, Journal of Functional Foods
      Citation Excerpt :

      Hence, effects of NMN and NMNP on 5-HTergic, GABAergic and immune systems were further investigated. A growing number of facts have demonstrated that 5-HT acts as an important sleep-promoting agent (Cespuglio, 2018; Murray, Buchanan & Richerson, 2015). Depletion of 5-HT could cause abnormality of the sleep/wake cycle (Kang et al., 2021).

    • Soporific effect of modified Suanzaoren Decoction on mice models of insomnia by regulating Orexin-A and HPA axis homeostasis

      2021, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      5-HTR1A is expressed in the presynaptic and postsynaptic neurons of hippocampus and raphe nucleus, limiting the release of 5-HT in nerve terminals and participating in the regulation of sleep [68,69]. In contrast, PCPA is an inhibitor of tryptophan hydroxylase, which can reduce 5-HT synthesis and lead to insomnia [70]. In this study, we confirmed that the 5-HT level and 5-HTR1A protein expression in the model group were significantly lower than those in the control group.

    View all citing articles on Scopus
    View full text