Long term biochemical changes in SERT compromised rats

When studying the role of serotonin in mood disorders there is an obvious paradox. We know that one of the most effective treatment for depression and anxiety disorders is blocking the SERT through selective serotonin reuptake inhibitors (SSRIs), leading to an increase in extracellular 5-HT. On the other hand, a genetic reduction in the SERT, which equally leads to increases in extracellular 5-HT, actually increased the risk of depression and anxiety disorder.

One possible explanation for this apparent paradox lies in the timing of the increases in extracellular 5-HT. Thus, in the case of a genetic reduction in SERT, 5-HT levels are increased already at a very early age. We know that 5-HT is critically involved in the development of the nervous system. It is therefore conceivable that the brain (and body) of genetically compromised SERT animals is fundamentally different from normal (so-called Wildtype) rats. However, since 5-HT plays such as broad role in development it is very hard to predict exactly what has changed in the SERT compromised animals.

In this project we therefore take a so-called “hypothesis-free” approach. So rather than setting a hypothesis a-priori about what may have changed, we aim to investigate as many changes as we can possible find. For that we take two different approaches: MALDI-MS and metabolomics. With MALDI-MS we carefully scan entire brain sections for regional changes in small molecules such as neurotransmitters and neurotransmitter metabolites. In metabolomics, we use brain or blood serum samples to investigate many different metabolites.

This project is in part supported by a grant from the Wellington Medical Research Foundation and is a collaboration with Drs Robert Keyzers and Bill Jordan.