Antagonism of serotonergic 5‐HT_2A/2C receptors: mutual improvement of sleep, cognition and mood?

Abstract

Serotonin [5-hydroxytryptamine (5-HT)] and 5-HT receptors are involved in sleep and in waking functions such as cognition and mood. Animal and human studies support a particular role for the 5-HT(2A) receptor in sleep, which has led to renewed interest in this receptor subtype as a target for the development of novel pharmacological agents to treat insomnia. Focusing primarily on findings in healthy human volunteers, a review of the available data suggests that antagonistic interaction with 5-HT(2A) receptors (and possibly also 5-HT(2C) receptors) prolongs the duration of slow wave sleep and enhances low-frequency (< 7 Hz) activity in the sleep electroencephalogram (EEG), a widely accepted marker of sleep intensity. Despite certain differences, the changes in sleep and the sleep EEG appear to be remarkably similar to those of physiologically more intense sleep after sleep deprivation. It is currently unclear whether these changes in sleep are associated with improved vigilance, cognition and mood during wakefulness. While drug-induced interaction with sleep must be interpreted cautiously, too few studies are available to provide a clear answer to this question. Moreover, functional relationships between sleep and waking functions may differ between healthy controls and patients with sleep disorders. A multimodal approach investigating subjective and objective aspects of sleep and wakefulness provides a promising research avenue for shedding light on the complex relationships among 5-HT(2A/2C) receptor-mediated effects on sleep, the sleep EEG, cognition and mood in health and various diseases associated with disturbed sleep and waking functions.

Sleep architecture in ziprasidone-treated bipolar depression: a pilot study

“…Ziprasidone's affinity for the reuptake sites is similar to that of the antidepressant imipramine, a drug that produces comparable changes in REM suppression in patients with depression [Gunasekara et al 2002]. The increase in REM latency may have also been mediated by 5-HT 1A agonism as agonists to postsynaptic receptors have been shown to inhibit REM sleep [Landolt and Wehrle, 2009]. Ziprasidone's sleep continuity properties might be related to its antihistaminergic and antidopaminergic activity.…”

A Review of Melatonin, Its Receptors and Drugs

“…4) TIK-301: It is a melatonergic agonist and serotonergic antagonist drug. It is a more powerful antagonist of serotonergic 5-HT 2c and 5-HT 2b receptors when compared to agomelatine [49]. Theoretically, it has an antidepressant effect.…”

Effects of the 5-HT_1A Receptor Agonist Tandospirone on ACTH-Induced Sleep Disturbance in Rats

“…28,29) Some studies in rats and humans have shown that 5-HT 2A receptor agonists increase wakefulness and inhibit slow-wave sleep (SWS), whereas 5-HT 2A receptor antagonists enhance duration of SWS and EEG low-frequency activity in non-REM sleep. [30][31][32] On the other hand, 5-HT 1A receptors were reported to regulate the activity of the serotonin nervous system, which inhibited the function of 5-HT 2A receptors. 33,34) Kitamura et al 28) demonstrated that 8-OH-DPAT, a potent agonist of 5-HT 1A receptors, inhibited ACTH-induced 5-HT 2A receptor hyperfunction.…”