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The Involvement of 5-HT2A Receptor in the Regulation of Sleep and Wakefulness, and the Potential Therapeutic Use of Selective 5-HT2A Receptor Antagonists and Inverse Agonists for the Treatment of an Insomnia Disorder

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5-HT2A Receptors in the Central Nervous System

Part of the book series: The Receptors ((REC,volume 32))

Abstract

Several agents have been shown to improve sleep induction and/or maintenance in patients with primary or comorbid insomnia. These include benzodiazepine and non-benzodiazepine receptor allosteric modulators, melatonin and the melatonin receptor agonist ramelteon, low dose doxepin, and suvorexant. However, benzodiazepines induce a further reduction of N3 sleep [slow wave sleep (SWS) or delta sleep] and rapid-eye-movement sleep (REMS), whereas values corresponding to these variables remain decreased during non-benzodiazepine, melatonin, ramelteon or low-dose doxepin administration. By contrast, suvorexant increases REMS. There is evidence indicating that non-selective (ritanserin, ketanserin, sertindole, ICI-170809, ICI-169369, RP-62203, SR-46349B) and selective (volinanserin, pruvanserin, eplivanserin) 5-HT2A receptor antagonists, as well as 5-HT2A receptor inverse agonists (nelotanserin, pimavanserin) increase SWS in laboratory animals and N3 sleep in subjects with normal sleep and/or patients with an insomnia disorder. Thus, the association of a selective 5-HT2A receptor antagonist or a 5-HT2A receptor inverse agonist with a hypnotic drug could be a valid alternative to normalize N3 sleep in patients with an insomnia complaint.

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Abbreviations

5-HT:

5-Hydroxytryptamine

BFB:

Basal forebrain

BZD:

Benzodiazepine

CNS:

Central nervous system

DRN:

Dorsal raphe nucleus

EEG:

Electroencephalogram

EMG:

Electromyogram

EOG:

Electro-oculogram

GABA:

γ-Aminobutyric acid

GAD:

Generalized anxiety disorder

LC:

Locus coeruleus

LDT:

Laterodorsal tegmental nucleus

LS:

Light sleep

MRN:

Median raphe nucleus

NREM:

Non-rapid-eye movement

PPT:

Pedunculopontine tegmental nucleus

REM:

Rapid-eye-movement

SE:

Sleep efficiency

SNc:

Substantia nigra pars compacta

SOL:

Sleep onset latency

SWS:

Slow wave sleep

TST:

Total sleep time

vPAG:

Ventral periaqueductal gray matter

VTA:

Ventral tegmental area

W:

Wakefulness

WASO:

Wake time after sleep onset

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Author information

Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, School of Medicine Clinics Hospital, University of the Republic, Montevideo, Uruguay

    Jaime M. Monti M.D.

  2. Somnogen Canada Inc., Toronto, ON, Canada

    Seithikurippu R. Pandi Perumal

  3. Sleep and Altertness Clinic, University Health Network, Toronto, ON, Canada

    D. Warren Spence

  4. Department of Physiology, School of Medicine, University of the Republic, Montevideo, Uruguay

    Pablo Torterolo

Authors
  1. Jaime M. Monti M.D.
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  2. Seithikurippu R. Pandi Perumal
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  3. D. Warren Spence
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  4. Pablo Torterolo
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Correspondence to Jaime M. Monti M.D. .

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Editors and Affiliations

  1. Faculté de Pharmacie, Université Paris Sud, Université Paris-Saclay, Chatenay-Malabry, France

    Bruno P. Guiard

  2. Department of Physiology and Biochemistry, University of Malta, Msida MSD, Malta

    Giuseppe Di Giovanni

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Monti, J.M., Pandi Perumal, S.R., Warren Spence, D., Torterolo, P. (2018). The Involvement of 5-HT2A Receptor in the Regulation of Sleep and Wakefulness, and the Potential Therapeutic Use of Selective 5-HT2A Receptor Antagonists and Inverse Agonists for the Treatment of an Insomnia Disorder. In: Guiard, B., Di Giovanni, G. (eds) 5-HT2A Receptors in the Central Nervous System. The Receptors, vol 32. Humana Press, Cham. https://doi.org/10.1007/978-3-319-70474-6_13

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