Tianeptine - Mechanism of Action

Mechanism of Action

Initial studies found that upon acute and sustained administration, tianeptine decreased the extracellular levels of serotonin. However tianeptine has low affinity for serotonin transporters, so this effect appears to be indirect. Further, the validity of the data from older studies has been contested on the basis of technical limitations; more recent studies found that long-term administration of tianeptine does not elicit any marked alterations (neither increases nor decreases) in extracellular levels of serotonin in rats, and tianeptine also had no effect on spontaneous firing rate of serotonergic neurons. However, coadministration of tianeptine and fluoxetine inhibited tianeptine's effect on long-term potentiation in hippocampal CA1 area. This is considered an argument for the opposite effects of tianeptine and fluoxetine on serotonin uptake.

In contrast to SSRIs and tricyclic antidepressants, tianeptine modestly enhances the mesolimbic release of dopamine, but it is also unclear how this occurs because tiapentine itself has no effect on dopamine transporters, nor does it affect D1, D2, D3, D4 and D5 receptors.

Perhaps the most studied hypothesis is that Tianeptine has a protective effect against stress induced neuronal remodeling. In animal models, tianeptine has been shown to inhibit the pathological stress-induced changes in glutamatergic neurotransmission in the amygdala and hippocampus. It also may facilitate signal transduction at the CA3 commissural associational synapse by altering the phosphorylation state of glutamate receptors. With the discovery of the rapid and novel antidepressant effects of drugs such as ketamine, it is increasingly being thought that the efficacy of many antidepressants is due in large part to their promotion of synaptic plasticity. This is believed to be achieved by regulating the excitatory amino acid systems that are responsible for changes in the strength of synaptic connections as well as enhancing BDNF expression, although this is all based largely on preclinical studies.