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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

  • Jaime M. Monti
  • Seithikurippu R. Pandi Perumal
  • D. Warren Spence
  • Pablo Torterolo
Chapter
Part of the The Receptors book series (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.

Keywords

Sleep Wakefulness REM sleep Slow wave sleep Serotonin 5-HT2A receptor antagonist 5-HT2A receptor inverse agonist Insomnia disorder 

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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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Jaime M. Monti
    • 1
  • Seithikurippu R. Pandi Perumal
    • 2
  • D. Warren Spence
    • 3
  • Pablo Torterolo
    • 4
  1. 1.Department of Pharmacology and Therapeutics, School of Medicine Clinics HospitalUniversity of the RepublicMontevideoUruguay
  2. 2.Somnogen Canada Inc.TorontoCanada
  3. 3.Sleep and Altertness ClinicUniversity Health NetworkTorontoCanada
  4. 4.Department of Physiology, School of MedicineUniversity of the RepublicMontevideoUruguay

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