Summary: A recent study examined how prucalopride, a medication known for its action on serotonin 5-HT4 receptors and commonly used as a laxative, alters resting brain activity in healthy adults and how these changes may relate to cognition and memory.
Researchers found that people who took low-dose prucalopride showed increased resting-state functional connectivity (rsFC) between key cognitive networks, suggesting a neural mechanism that could explain previously observed improvements in attention, memory, and other cognitive functions.
These findings add evidence that drugs targeting the 5-HT4 serotonin receptor, including prucalopride, may have promise as treatments for cognitive impairment and as adjunctive therapies in mood disorders.
Key Facts:
- Prucalopride, while used primarily as a laxative, has been shown at low doses to enhance aspects of cognition and memory in humans.
- The drug increased functional connectivity among brain networks involved in executive control and attention, which supports improved information processing.
- At the same time, prucalopride reduced connectivity within the default mode network, a pattern associated with decreased mind-wandering and more focused cognitive processing.
Source: Elsevier
Cognitive impairment frequently co-occurs with mood and psychiatric disorders and can persist even after mood symptoms improve, causing considerable disability.
Few pharmacological options specifically target cognitive deficits. Preclinical and early human studies have highlighted 5-HT4 receptor agonists, such as prucalopride, as potential pro-cognitive agents. Until now, however, the drug’s effects on resting brain activity in people were not well understood.
A new study published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging investigated how prucalopride influences resting-state connectivity in healthy adult volunteers.
5-HT4 serotonin receptors are found in brain regions that support cognition and mood regulation, including the frontal cortex, basal ganglia, and hippocampus. These receptors are distinct from other serotonin targets and have been linked to learning and memory processes.
In the reported study, 50 healthy volunteers were randomized in a double-blind design: 25 received prucalopride (1 mg daily for six days) and 25 received placebo. Participants completed resting-state functional MRI scans in which they lay awake and relaxed inside the scanner.
Lead author Angharad de Cates, PhD, MRCPsych (University of Oxford), noted that earlier trials showed low clinical doses of prucalopride can improve cognition and memory in healthy volunteers, and that this study helps reveal the neural changes that could underlie those benefits.
Compared with placebo, the prucalopride group showed greater rsFC between major cognitive networks. Specifically, connectivity increased between the central executive network—important for active thought and problem solving—and regions of the posterior and anterior cingulate cortex (PCC and ACC), which support attention and information processing.
Additional analyses revealed stronger connectivity between the rostral ACC (both left and right) and the left lateral occipital cortex, a visual area involved in directing attention toward relevant objects. Conversely, the drug reduced connectivity within the default mode network (DMN), which is typically active during mind-wandering and internally focused thought.
Dr. de Cates commented that these changes indicate prucalopride influences specific brain circuits to enhance cognitive function—sometimes increasing connectivity where integration is needed and decreasing connectivity where disengagement from internally focused processes supports task focus.
Joint senior author Susannah Murphy, PhD, added that balanced connectivity within and between these networks is essential for healthy cognition and is often disrupted in depression. On the day of scanning, participants who took prucalopride also performed better on cognitive tests than those given placebo, suggesting that the observed rsFC changes may serve as a neural signature of pro-cognitive action.
Untreated cognitive symptoms significantly reduce quality of life for people with depression. This study supports the view that 5-HT4 receptor agonists could represent a novel approach to treating cognitive impairment in psychiatric populations.
Catherine Harmer, PhD, noted that the results reinforce earlier data showing prucalopride’s effects on brain circuits involved in learning and memory, pointing to potential clinical applications as a cognitive-enhancing treatment.
Cameron Carter, MD, editor of the journal, stated that the findings, which show modulation of resting-state networks by a 5-HT4 receptor agonist, align with prior evidence that prucalopride affects brain systems engaged during focused, higher-level cognitive activity and may have therapeutic potential.
About this neuropharmacology, serotonin, and cognition research news
Author: Eileen Leahy
Source: Elsevier
Contact: Eileen Leahy – Elsevier
Image: The image is credited to Neuroscience News
Original Research: Open access. “5-HT4 receptor agonist effects on functional connectivity in the human brain; Implications for pro-cognitive action” by Angharad de Cates et al., Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. DOI: 10.1016/j.bpsc.2023.03.014
Abstract
5-HT4 receptor agonist effects on functional connectivity in the human brain; Implications for pro-cognitive action
Background
Cognitive deficits commonly accompany mood disorders and can persist after mood symptoms subside, causing lasting impairment. There are currently limited pharmacological options that directly target these cognitive problems. 5-HT4 receptor agonists have shown pro-cognitive promise in animal models and early human studies. Because optimal cognitive performance is linked to appropriate resting-state connectivity among specific neural networks, understanding how 5-HT4 receptor agonism influences rsFC in humans is important.
Methods
We obtained resting-state fMRI scans from 50 healthy volunteers in a randomized, double-blind study: 25 participants received prucalopride (1 mg daily for six days) and 25 received placebo.
Results
Network analyses revealed that the prucalopride group had increased rsFC between the central executive network (cEN) and regions of the posterior and anterior cingulate cortex (PCC/ACC). Seed-based analyses also showed stronger connectivity between bilateral rostral ACC and the left lateral occipital cortex, along with reduced rsFC between the hippocampus and other default mode network regions.
Conclusions
Low-dose prucalopride in healthy volunteers appears to enhance connectivity between regions involved in cognitive control while reducing connectivity within the default mode network, a pattern similar to other pro-cognitive agents. These neural changes provide a plausible mechanism for the cognitive benefits previously observed with 5-HT4 receptor agonists and support further investigation of these agents in clinical psychiatric populations.