Animal Study Suggests Potential Role of Serotonin Receptor Agonist

As scientists investigate the fast-acting properties of pharmacological agents that are independent of the serotonergic system, such as ketamine, a study published in the January 22 Neuropsychopharmacology shows that such investigation could be on the horizon for the fourth subtype of serotonin receptors, 5-HT4.

In a collaborative effort, researchers from the University of Paris-Sud and Columbia University evaluated the antidepressant and anxiolytic properties of a 5-HT4 receptor agonist, RS67333, in an animal model of anxiety and depression.

“An increase in the density of 5-HT4 receptors has been reported in cortical and striatal tissue of postmortem brain samples from patients diagnosed with major depression,” Denis David, Ph.D., coauthor and an assistant professor of psychopharmacology at the University of Paris-Sud, told Psychiatric News. “Furthermore, an association has been reported for single nucleotide polymorphisms of the 5-HT4 receptor gene in patients with unipolar depression.”

According to David, many of the currently approved serotonergic-associated antidepressants—which focus primarily on the serotonin transporter protein (SERT)—are often limited by a degree of nonresponsiveness among patients and exhibit delayed onset of therapeutic efficacy. Because of these limitations with SSRIs, David said that the development of new antidepressants is of utmost importance and that understanding the mechanisms underlying the delayed onset should offer insights into new approaches.

To investigate the importance of 5-HT4 in alleviating symptoms of mood disorders, David and colleagues used a mouse model in which the hypothalamic-pituitary-adrenal axis was blunted—resulting in characteristics of depression and anxiety. Comparisons were made between animals that were given a one-month treatment of the RS67333 compound or fluoxetine.

Results showed that chronic treatment with either RS67333 or fluoxetine achieved anxiolytic and antidepressant-like activity in animals. However, these effects were observed after seven days in animals treated with the RS67333 and 14 days in animals treated with fluoxetine. The researchers also found that by making the 5-HT4 receptors nonfunctional, both RS67333 and fluoxetine lost the ability to reduce depression and anxiety—suggesting that 5-HT4 receptors may be essential in fluoxetine’s effect on behavior.

“Our results show, for the first time, in a model of anxiety and depression, that a 5-HT4 receptor agonist may be a fast-acting anxiolytic agent and that 5-HT4 stimulation is necessary for the behavioral effects of fluoxetine, a classic SSRI antidepressant,” the researchers wrote. They speculated that fluoxetine may act slowly in comparison to relieve depression and anxiety symptoms because it indirectly targets 5-HT4—unlike RS67333.

Currently, 5-HT4 stimulators are approved by the Food and Drug Administration for the treatment of multiple gastrointestinal disorders, such as gastritis and irritable bowel syndrome. According to David, 5-HT4 receptor agonists have never been tested as a treatment option for patients with major depressive disorder. He said that subsequent clinical trials will be needed to confirm the current findings in humans.

Christopher Kratochvil, M.D., associate vice chancellor for clinical research and chief medical officer at the University of Nebraska Medical Center, told Psychiatric News that clinician scientists can benefit from the study’s discoveries.

“Certainly an animal model like this has limitations on multiple levels in its application to human research, so this study is an early step in better understanding potential approaches to treating anxiety and depression. However, a translational study such as this can help to inform, guide, and motivate additional work in exploring novel mechanisms associated with anxiolytic and antidepressant properties of 5-HT4 receptor agonists,” commented Kratochvil.

Agreeing with the authors, Kratochvil concluded that the current findings give hope to clinical researchers and those with mental illness of one day having a faster-acting alternative for the treatment of depression and comorbid anxiety.

The study was funded by the Brain and Behavior Research Foundation. ■

An abstract of “Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism” can be accessed here.