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A new study examining the drug Prucalopride finds it has effects in areas of the human brain that improve cognitive function.

This figure shows that healthy participants who received prucalopride had greater functional connectivity between key cognitive regions (the posterior / anterior cingulate cortices) and a major cognitive network (the central executive network). © Oxford University/Biological Psychiatry
This figure shows that the healthy participants who received prucalopride had greater functional connectivity between key cognitive regions (the posterior/anterior cingulate cortices) and a major cognitive network (the central executive network).

Cognitive deficits accompany mood disorders and other psychiatric conditions, often with debilitating effects. Limited treatments currently exist, but studies in animals and humans have pointed to drugs that activate serotonin receptors as a potential therapeutic for the symptoms. However, it has remained unclear how the medication affects resting brain activity.

Now, a new study in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, led by researchers in the Department of Psychiatry at the University of Oxford, examines the drug’s effects in healthy human adults.

Serotonin receptors and the 5-HT4-type receptors in particular are found in areas throughout the brain, including the frontal cortex, basal ganglia and hippocampus, that are known to mediate cognitive function and regulate mood. Serotonin receptors are the primary targets of anti-depressant medications, but resolving mood disturbances often does not resolve cognitive symptoms.

The researchers enlisted 50 healthy volunteers; half of them received a six-day course of prucalopride, a highly selective agonist of the 5-HT4 type serotonin receptor, whereas the other half of the participants received a placebo. Participants underwent scanning with functional magnetic resonance imaging (fMRI), including a “resting scan” where they could relax in the scanner.

Lead author Dr Angharad de Cates said:

“Our previous studies on prucalopride demonstrated that even at low clinical doses it can improve cognition and memory in healthy volunteers. This latest research provides a neurological mechanism by which this might occur.”

Participants who received the medication displayed more functional connectivity in their resting state (rsFC) between major cognitive networks. This included more rsFC between the central executive network (cEN), a brain network used for processing thoughts, and the posterior and anterior cingulate cortex (PCC/ACC), brain areas that regulate information processing and attention in the brain. There was also more rsFC between regions of the ACC and the lateral occipital cortex, a region that helps us pay attention to objects that matter. What’s more, medicated participants compared to placebo controls showed decreased rsFC within the default mode network (DMN), a brain network that is activated during mind wandering.

Appropriate connectivity between and within these brain networks is needed to think properly, and it’s known that this connectivity is abnormal in depression. As these same participants taking prucalopride had better scores on cognitive tests earlier that day compared to the placebo participants, this pattern of changes with prucalopride (i.e. increased rsFC within cognitive networks and decreased rsFC within the DMN) appears to be a “signature” of a drug that improves cognition.

Dr. de Cates added:

“This provides further evidence that prucalopride is having an effect in areas of the brain that improve cognitive function – both by increasing and reducing connectivity between specific brain regions as required.”

Susannah Murphy, Associate Professor and joint senior author of the study, said: “Untreated cognitive problems have a significant impact on the quality of life of people with depression. This study adds to the growing evidence base that drugs affecting the 5-HT4 serotonin receptor hold promise as a novel way to treat depression and cognitive impairment.” 

Catherine Harmer, Professor of Cognitive Neuroscience and joint senior author of the study, said: “This study adds to the evidence base that the common laxative treatment prucalopride can have important effects in the brain, particularly affecting circuits which are important for learning and memory. Together with previous data, this suggests that this drug might be useful as a pro-cognitive treatment in disorders such as depression.”