5-HT4 receptor agonist effects on functional connectivity in the human brain; Implications for pro-cognitive action.

BACKGROUND: Cognitive deficits are often comorbid with mood disorders, and can cause significant functional impairment even after resolution of the primary mood symptoms. We do not currently have pharmacological treatments that adequately address these deficits. 5-HT4 receptor agonists show promise as potential pro-cognitive agents in animal and early human translational studies. Optimal cognitive performance in humans is directly associated with appropriate functional connectivity between specific resting state neural networks. However, so far the effect of 5-HT4 receptor agonism on resting-state functional connectivity in the brain in humans is unknown. METHODS: We collected resting state fMRI scans from 50 healthy volunteers; 25 of whom had received six days x 1mg prucalopride (a highly-selective 5-HT4 receptor agonist) and 25 who had received placebo in a randomised double-blind design. RESULTS: Network analyses identified that participants in the prucalopride group had enhanced resting-state functional connectivity (rsFC) between the central executive network (cEN) and the posterior / anterior cingulate cortex (PCC / ACC). Seed analyses also showed greater rsFC between the left and right rostral ACC and the left lateral occipital cortex ACC, and reduced rsFC between the hippocampus and other default mode network regions. CONCLUSIONS: Similar to other potentially pro-cognitive medications, low-dose prucalopride in healthy volunteers appears to enhance rsFC between regions involved in cognitive networks and reduce rsFC within the DMN. This suggests a mechanism for the behavioural cognitive enhancement previously seen with 5-HT4 receptor agonists in humans and supports the potential for 5-HT4 receptor agonists to be used in clinical psychiatric populations.