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. MontiEmail author
  • Seithikurippu R. Pandi Perumal
  • D. Warren Spence
  • Pablo Torterolo
Part of the The Receptors book series (REC, volume 32)


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.


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





Basal forebrain




Central nervous system


Dorsal raphe nucleus








γ-Aminobutyric acid


Generalized anxiety disorder


Locus coeruleus


Laterodorsal tegmental nucleus


Light sleep


Median raphe nucleus


Non-rapid-eye movement


Pedunculopontine tegmental nucleus




Sleep efficiency


Substantia nigra pars compacta


Sleep onset latency


Slow wave sleep


Total sleep time


Ventral periaqueductal gray matter


Ventral tegmental area




Wake time after sleep onset


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Jaime M. Monti
    • 1
    Email author
  • 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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