Effects of 5HT3 Receptor Antagonism by Tropisetron on the Sleep EEG and on Nocturnal Hormone Secretion

Abstract

Two dosages (5 mg and 25 mg) of the selective 5HT3 receptor antagonist tropisetron (lCS 205-930) were administered to healthy male controls, and the effects on the sleep EEG and nocturnal secretory activity of growth hormone (GH) and cortisol were evaluated. The lower dosage was administered to four subjects and the higher dosage to eight on 5 consecutive days, preceded and followed by 2 days of placebo treatment. After 25 mg of tropisetron, there was a slight increase in REM sleep in the first part of the sleep period, and stage 2 was decreased during the total night. In addition, plasma cortisol levels increased earlier than under placebo, and plasma GH levels were reduced in the second part of the night. Thus, only discrete effects of tropisetron upon sleep-endocrine activity were noted, making it unlikely that serotoninergic neurotransmission exerts its well documented effects upon sleep through 5HT3 receptors.

Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 1, a pharmacokinetic/pharmacodynamic comparison with paroxetine in healthy men

“…It has been suggested that 5-HT 3 receptor agonism might suppress REM in rodents ( Monti and Jantos, 2008 ; see also companion paper Leiser et al, this issue) and humans ( Staner et al, 2001 ) and that 5-HT 3 receptor antagonism may decrease ROL in humans ( Rothe et al, 1994 ). These effects in humans are modest but most likely contribute to our results, as the very high affinity of vortioxetine for the 5-HT 3 receptor means that even at low plasma concentrations this receptor is likely to be saturated ( Bang-Andersen et al, 2011 ).…”

“…The effects of the other receptor interactions of vortioxetine are less well understood. 5-HT 3 antagonists have been shown to shorten REM latency whereas 5-HT 3 agonists may lengthen it, both in rodents and in humans ( Adrien et al, 1992 ; Monti and Jantos, 2008 ; Rothe et al, 1994 ; Staner et al, 2001 ). A 5-HT 7 antagonist suppressed REM sleep and increased ROL in both rodents and humans ( Bonaventure et al, 2012 ).…”

Early Decision-Making in Drug Development: The Potential Role of Pharmaco-EEG and Pharmaco-Sleep

“…However, an alternative interpretation is to conclude that EEG is likely to be sensitive to pharmacological modulation of all the major neurotransmitter systems and hence to provide a useful PD signal, but that the observed effects will often be downstream due to the complexity of the neurological networks, and hence the exact mechanism is hardly ever known. The complexity of the homeostatic processes also means that the effect size may vary for different mechanisms (for example, EEG has a high sensitivity to the effects of benzodiazepines [11] and scopolamine [12] but a lower sensitivity to the selective serotonin re-uptake inhibitors [13]) and also in different vigilance states (for example, the 5-HT 3 receptor antagonists have effects on the EEG during sleep [14] but not during the daytime [15]). Also, in some cases, such as for 5-HT 2a antagonists [16], sleep architecture changes may be more sensitive than the spectral EEG end points.…”