Abstract
5-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. Forty 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. Prucalopride 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. These 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.
Highlights
Animal studies have suggested that 5-HT4 receptor agonists have pro-cognitive and antidepressant-like effects, and this study represents an important step in translating these findings to humans using an experimental medicine approach
Consistent with the effects of 5-HT4 agonism in animals, acute prucalopride had a procognitive effect in healthy volunteers across three separate tasks: increasing word recall in an explicit verbal learning task; increasing the accuracy of recall and recognition of words in an incidental emotional memory task; and increasing the probability of choosing a symbol associated with high probability of reward or absence of loss in a probabilistic instrumental learning task
On the emotional recall and recognition tasks, as well as the second wordlist of the AVLT, there was a pattern of decreased false alarms/intrusions in the prucalopride group, suggesting that 5-HT4 receptor agonism increases the precision of memory
Summary
5-HT4 receptor activation has been shown to upregulate hippocampal cell proliferation and increase the expression of neuroplasticity-related proteins such as cyclic AMP response element binding and brainderived neurotrophic factor (Lucas et al, 2007; Pascual-Brazo et al, 2012), effects which mirror those seen with clinically effective antidepressants (Harmer et al, 2017) Consistent with this neurobiological profile, 5-HT4 partial agonists have a facilitatory effect on rodent behavioural tests of learning and memory (King et al, 2008; Hagena and Manahan-Vaughan, 2017), and in particular hippocampal-dependent learning and memory (Hagena and Manahan-Vaughan, 2017), including pro-cognitive effects on spatial learning (Fontana et al, 1997; Lelong et al, 2001), place recognition (Lamirault and Simon, 2001; Orsetti et al, 2003) and object recognition (Lamirault and Simon, 2001; Levallet et al, 2009). Consistent with this, studies in rodents have demonstrated that 5-HT4 receptor agonists exert antidepressant-like effects
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