A role for 5-HT₄ receptors in human learning and memory

Abstract

Background5-HT4 receptor stimulation has pro-cognitive and antidepressant-like effects in animal experimental studies; however, this pharmacological approach has not yet been tested in humans. Here we used the 5-HT4 receptor partial agonist prucalopride to assess the translatability of these effects and characterise, for the first time, the consequences of 5-HT4 receptor activation on human cognition and emotion.MethodsForty one healthy volunteers were randomised, double-blind, to a single dose of prucalopride (1 mg) or placebo in a parallel group design. They completed a battery of cognitive tests measuring learning and memory, emotional processing and reward sensitivity.ResultsPrucalopride increased recall of words in a verbal learning task, increased the accuracy of recall and recognition of words in an incidental emotional memory task and increased the probability of choosing a symbol associated with a high likelihood of reward or absence of loss in a probabilistic instrumental learning task. Thus acute prucalopride produced pro-cognitive effects in healthy volunteers across three separate tasks.ConclusionsThese findings are a translation of the memory enhancing effects of 5-HT4 receptor agonism seen in animal studies, and lend weight to the idea that the 5-HT4 receptor could be an innovative target for the treatment of cognitive deficits associated with depression and other neuropsychiatric disorders. Contrary to the effects reported in animal models, prucalopride did not reveal an antidepressant profile in human measures of emotional processing.

Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: Analysis from a phase 3 long-term extension study in children/young adults with Dravet syndrome

“…Although the current analysis focused on changes in seizure frequency and impact on everyday EF, the results cannot rule out the possibility of an additional independent mechanism of action of fenfluramine for everyday EF. It is important to note that the wellknown serotonergic effects of fenfluramine-in particular, its effects on the 5HT 4 receptor-may also play a role in the positive changes observed in EF and cognition [53][54][55]. Furthermore, preclinical studies have shown that fenfluramine has positive modulatory activity at sigma-1 receptors, which contributes to both antiseizure activity and positive effects on EF in zebrafish and mouse models [53,55].…”

Central 5-HT receptors and their function; present and future

“…Aside from rodent studies, there is an earlier report that the 5-HT 4 receptor agonist RS 17017 improved the cognitive performance in non-human primates (Terry et al, 1998). More recently in a study of healthy human volunteers, a single dose of the 5-HT 4 receptor agonist prucalopride was found to have pro-cognitive effects in a battery of learning and memory tests, although the drug was not active in models of emotional processing that have antidepressant predictive capability (Murphy et al, 2019). Although exploratory in nature, the latter study reported relatively mild adverse effects of prucalopride, in particular headache, nausea and diarrhoea, and consistent with that expected of agents with 5-HT 4 receptor agonist actions.…”

Therapeutic modulators of the serotonin 5-HT4 receptor: a patent review (2014-present)

“…Therefore, the interest of 5-HT 4 R agonist have been investigated to treat depressive disorders [26]. Despite first negative results regarding prucolopride anti-depressant effects [27] several 5-HT 4 R ligands are still investigated in clinical trials including prucalopride 3, Revexepride 10 and PF-04995274 17 [26].…”