Psychiatric drugs have therapeutic potential.
Cognitive impairment often coexists with mood disorders and other psychiatric disorders, often causing significant difficulties. Currently, only a limited number of treatments are available, but animal and human studies suggest that drugs such as prucalopride, a laxative that activates serotonin receptors, may have potential therapeutic benefits for these symptoms. However, it is not known how this drug affects brain activity at rest. New research in Biological Psychiatry: Cognitive Neuroscience and Neuroimagingpublished by Elsevier, is currently investigating the effects of this drug in healthy adults.
Serotonin receptors, especially 5-HT4receptors of the type, are widely distributed in various regions of the brain, including the frontal cortex, basal ganglia and hippocampus. These areas play an important role in cognitive function and mood regulation. Serotonin receptors are the main targets of antidepressants, but treating mood disorders does not necessarily reduce cognitive symptoms.
The researchers recruited 50 healthy volunteers, half of whom received a six-day treatment with prucalopride, a highly selective agonist of 5-HT.4 type of serotonin receptor, while the other half of the participants received a placebo. Participants underwent active MRI scans, including a “resting scan” where they relaxed in the scanner.
Lead author Angharad de Cates, Ph.D., MRCPsych, at the University of Oxford, said of the work: “Our previous studies of prucalopride showed 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 may occur.
The drug-treated participants showed greater resting-state functional connectivity (rsFC) between key cognitive networks. This included more rsFC between the central executive network, a brain network used to process thoughts, and the posterior and anterior cingulate cortex (ACC), brain regions that control information processing and attention in the brain. There was also more rsFC between areas of the ACC and the lateral occipital cortex, an area that helps us pay attention to things that matter. In addition, drug-treated participants compared to placebo controls showed reduced rsFC in the default network, a brain network activated during mind wandering.
Dr. de Cates added, “This provides further evidence that prucalopride affects brain regions that improve cognitive function—both by increasing and decreasing connectivity between specific brain regions as needed.”
Susannah Murphy, Ph.D., associate professor and lead author of the study, said: “Proper connectivity between and within these brain networks is required to think correctly, and this connectivity has been shown to be abnormal in depression.” Here, participants taking prucalopride had better scores on cognitive tests on the day of the scan compared to placebo participants. It suggests that the changes in rsFC we observed with prucalopride may serve as a ‘signature’ of a cognitive-enhancing drug.”
Dr. Murphy continued, “Untreated cognitive problems have a significant impact on the quality of life of people with depression. This study adds to the growing body of evidence that drugs that affect 5-HT4 Serotonin receptors hold promise as a new way to treat depression and cognitive impairment.
Catherine Harmer, Ph.D., professor of cognitive neuroscience and lead author of the study, said: “This study adds to the evidence that the common laxative prucalopride can have important effects on the brain, particularly affecting circuits that are important.” for learning and memory. Combined with previous data, this suggests that this drug may be useful as a cognitive therapy for conditions such as depression.
Cameron Carter, MD, Editor Biological Psychiatry: Cognitive Neuroscience and Neuroimagingsaid of the work, “These data demonstrate modulation of resting-state connectivity in the brain by 5-HT4 receptor agonist and purported cognitive enhancer prucalopride, add to previous evidence that the drug modulates brain systems involved in targeted, higher cognitive function and may have therapeutic potential.
Reference: “Effects of 5-HT4 receptor agonists on functional connectivity in the human brain: implications for cognitive function” by Angharad N. de Cates, Marieke AG Martens, Lucy C. Wright, Daisy Gibson, Gershon Spitz, Cassandra D. Gould van Praag , Sana Suri , Philip J. Cowen, Susannah E. Murphy, and Catherine J. Harmer, 23 Apr. 2023, Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.
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