Could a New Probe Unlock Serotonin’s Secrets in Depression?

When it comes to depression, serotonin plays a significant role in drug development, diagnosis, and treatment. A Chinese team has recently created a fluorescent probe for imaging processes that is highly selective and sensitive to serotonin in order to better investigate this field. They present their initial findings from animal and cell models in the journal Angewandte Chemie.

A Global Public Health Concern

Across the globe, depression is a serious public health issue. Current treatments are inadequate primarily because researchers do not well understand the mechanisms underlying depression. Recent research suggests that low serotonin levels are not the only factor contributing to depression.

Innovative Research from Guangxi University

A group from Guangxi University in China, under the direction of Weiying Lin, sought to create a highly specific molecular fluorescent probe to investigate the function of serotonin in depression. However, serotonin shares many structural and chemical similarities with other biomolecules, including tryptophan and melatonin, complicating these investigations. Precise studies have shown minute variations in reactivity among these molecules.

Development of a Selective Molecular Probe

The group created 3-mercaptopropionate, a unique reactive group that reacts with serotonin in a very specific manner in a cascade reaction. The researchers coupled this reactive building block with a luminous dye, a derivative of dicyanomethylene-benzopyran. When the “appendage” attaches, the probe is initially turned “off.”

The probe first reacts with serotonin via a thiol-ene click reaction, where the reactive building block’s SH group attaches to a double bond in serotonin. Next, a second bond is created through a nucleophilic reaction between the reactive building block’s carbonyl group and the amino group in serotonin, facilitated by proximity. As a result, the fluorescent dye loses its building component, and its fluorescence is turned “on.” This allows for the sensitive and selective detection of serotonin, even inside cells.

Insights from Imaging Neuron Cell Lines

Using the probe, the researchers imaged a neuron cell line that can serve as a model for depression through corticosteroid therapy. Both the “depressed” and normal cells revealed almost the same amount of serotonin. However, in response to stimulation, the depressed cells were able to release noticeably less serotonin.

Implications of Current Antidepressant Treatments with the Probe

The use of serotonin reuptake inhibitors, the current class of antidepressants, marginally boosted the release of serotonin in these cells. One theory links a decreased capacity to produce serotonin to mTOR, a biomolecule involved in numerous cellular signaling pathways.

mTOR’s Role in Serotonin Release

The researchers observed that while mTOR inhibitors lowered serotonin release from normal cells, mTOR activators dramatically increased serotonin release in depressed cells. The neuron and mouse models allowed for the confirmation of all findings.

Key Takeaways on Depression Mechanisms and the Probe

These imaging findings imply that the main determinant in the depression model is not the serotonin level itself. Rather, serotonin release from neurons appears to be far more important. This capacity has a substantial correlation with mTOR activity, which may indicate future developments in the treatment of depression.