The tightly regulated balance between secretion and removal of neurotransmitters is not functioning properly in certain mental conditions like bipolar disorder, obsessive-compulsive disorder, anxiety, and depression. Neurotransmitters are signaling molecules used to transmit messages between neurons (nerve cells) in the brain. Serotonin is one of the neurotransmitters affected in depression and similar disorders. The most common class of drugs for the treatment of these conditions is called selective serotonin reuptake inhibitors (SSRI). The well-known Fluoxetine (Prozac) is a member of this class.

SSRIs work on the serotonin balance by inhibiting a transporter called SERT that selectively pumps serotonin back into the neurons. The action of the SERT molecule shortens the time that serotonin has to deliver its signal, inhibiting SERT therefore increases serotonin function. How exactly SSRIs inhibits SERT has not been clear until now, even though researchers knew that the mechanism cannot just be a simple binding to SERT and thus preventing SERT from binding to serotonin. If this were the case, the action of the drugs should kick in fully at latest a few days after the patient started taking them. One of the most perplexing properties about SSRIs, however, is that it can take weeks to months before they are fully active. Researchers therefore believed since a long time that SSRIs inhibit the SERT in a different way. Still, the exact mechanism was not known until now.

In a recent publication in Science, a team of researchers showed a possible mechanism of action for Fluoxetine. According to these scientists, it works through a completely new inhibitory pathway, which can also explain the lengthy and for patients often very frustrating waiting time before SSRIs work clinically. They found that in mice chronically fed with Fluoxetine, the expression of the gene that encodes the blueprint of SERT is reduced, which means less SERT is available to remove serotonin from the synapse. This is a surprising finding in itself, still, the mechanism how Fluoxetine down-regulates the SERT expression is even more surprising.

Gene expression works in two steps: DNA, the genetic material is copied into a working draft in the form of RNA, called messenger or mRNA. Proteins, which are the building blocks of our cells are then read from this RNA-copy of the gene. The mRNA is highly unstable, and its degradation ensures that no more new protein than necessary is produced. Until recently, scientists believed that gene expression is regulated by proteins that bind to the DNA telling the gene-expression-machinery directly where and how often to read the blueprint to make a new protein. Newer research shows that this is not the only way to regulate gene expression, and a very important component of gene regulation takes place a later point, when the mRNA  is translated into a new protein. Non-protein encoding RNA molecules called micro-RNAs can also regulate how often a gene is read or they regulate how long the mRNA molecule sticks around before it gets degraded. This determines how much protein is produced from this mRNA molecule.

The researchers now showed that a newly found micro-RNA called micro-RNA 16 decreases SERT expression. In the Fluoxetine-fed mice, Fluoxetine increased the expression of this micro RNA. As a result, lower levels of SERT were produced, leading to prolonged serotonin action. This mechanism only affects the levels at which new SERT molecules are produced. SERT already present in the neuron is unaffected, so that the effect of the drug will only be noticeable after several weeks of taking it, when old worn-out SERT molecules are replaced at a lower rate than what they would be without Fluoxetine.

Reference

Baudry A, Mouillet-Richard S, Schneider B, Launay JM, & Kellermann O (2010). miR-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants. Science (New York, N.Y.), 329 (5998), 1537-41 PMID: 20847275