Tianeptine: Tricyclic Antidepressants (Tcas)

Tianeptine is a member of the class of drugs known as tricyclic antidepressants (TCAs). It has been found to have anxiolytic and mood altering effects. Despite being a tricyclic drug, tianeptine has a significantly different pharmacologic profile than the average TCA and is thought to produce effects through action at several unique receptors. Tianeptine has found use in the treatment of asthma and irritable bowel syndrome (IBS) and may affect neural plasticity (learning).

Potential Benefits of Tianeptine

Tianeptine has been primarily used to treat depression, with some off-label use in the treatment of asthma and IBS. Following reports of improved cognition and euphoria from patients, researchers began to find that tianeptine had unique
properties not seen with other TCA drugs. Subsequent research, particularly into interactions with receptors, indicates that tianeptine may dramatically affect human cognition, mood, and learning with very few side effects.

Depression, Stress, and Neuroplasticity

Neuroplasticity is a term used to describe the brain’s ability to adapt and change structure in response to learning and novel situations. In short, increased neuroplasticity is associated with easier learning and better cognitive performance while decreased neuroplasticity has opposite effects. Depression contributes to decreased neuroplasticity, so it should come as no surprise that depression impacts cognitive performance and that antidepressants can improve neuroplasticity.

One of the major factors contributing to depression is anxiety, which is provoked by stress.
Multiple studies over many years have confirmed that stress and anxiety are detrimental to learning. Indeed, anyone who has ever been peppered with questions in a high-pressure environment (e.g. testing, medical students on wards, etc.) can attest to the cognitive impairment that results from stress. The problem is even worse than that, however. Stress can actually induce neuronal remodeling and affect established brain chemistry. There is evidence that stress, if allowed to persist, can actually lead to permanent mental
impairment.

Antidepressants and other neuromodulatory compounds can protect against stress-induced neuronal remodeling. While the benefits of antidepressants on neuronal function have been known for some time, renewed interest has developed due to reports regarding tianeptine. There is good evidence to indicate that tianeptine inhibits pathological changes in glutamine transmission in the amygdala and hippocampus[1]. By doing this, tianeptine can reduce the effects of stress on the brain, making it easier to work in, function in, and survive high-stress environment.

Receptor Activation

Tianeptine has myriad receptor interactions that produce a wide range of effects. Beyond elevating mood and reducing anxiety, the molecule has also been found to have anticonvulsant and analgesic effects. It is also thought to induce euphoria, an effect that may explain the drug’s antidepressant effects despite a relatively mild serotonin effect.

What is clear about tianeptine is that it is a complex drug involved in multiple receptor interactions. Pinning down the precise effects of tianeptine as a result of specific receptor interactions has been difficult. Here is what has been discovered about the drug thus far.

Glutamate Receptors
Glutamate is a non-essential amino acid that plays an important role in neurotransmission and neural activation. In fact, glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system and is heavily involved in learning and memory[2]. There are several different glutamate receptors in the central nervous system (CNS), including the NMDA receptor and the AMPA receptor.

NDMA receptor activation plays a vital role in learning and memory as well as in alertness.
Many anesthetic drugs, like ketamine and nitrous oxide, reduce NMDA receptor activity. When activity is increased, as is the case with tianeptine binding, the NMDA receptor enhances memory and learning through a Hebbian mechanism. This essentially means that it promotes synaptic development and thus enhances the formation of connections between one neuron and another.

AMPA receptor activation mediates fast synaptic transmission in the CNS. This effect plays a significant role in long-term potentiation (LTP), which is the process of strengthening of synapses based on recent patterns of activity. In other words, AMPA receptor activation helps to strengthen synaptic connections and thus helps to make newly learned tasks and facts more permanent. It is a factor in long-term memory formation.

Tianeptine alters glutamate activity at both of the above receptors and, in so doing, may boost memory and learning. It also promotes the release of brain-derived neurotrophic factor (BDNF), which promotes nerve and synapse growth and is associated with the formation of new memories and the protection of existing brain structure[3], [4]. BDNF is heavily associated with the cognitive-enhancing effects of physical
activity[5].

Adenosine A1 Receptors
Adenosine A1 receptors are thought to inhibit cholinergic neurons in the basal forebrain, an effect associated with increasing sleepiness and decreased alertness[6]. The receptors have also been associated with anticonvulsant and analgesic activity. Stimulants tend to antagonize (suppress activity) A1 receptors while sedatives tend to increase activity and thus reduce seizure activity and raise seizure thresholds (i.e. the amount of aberrant brain activity needed to trigger a seizure).

Tianeptine appears to modify the downstream effects of A1 receptors, which means the drug works not at the receptor itself, but by modifying the chain of events that follow after receptor activation. In so doing, tianeptine may be able to suppress seizure activity and produce analgesic effects without producing the reduction in alertness associated with these events.