Neuromediator Serotonin Is Linked To Major Neurological Disorders, Depression And Suicidal Behaviour

Our brain is a remarkably complex system. This makes the fact that major aspects of our behavior can be controlled by changes in the production of some small molecules quite remarkable. But here it is: neuromediator serotonin is involved in so many different circuits of our brain that we only recently started to get the picture into focus.

Serotonin (5-HT, 5-hydroxytriptophan) is a monoamine neurotransmitter from the group of biogenic amines. Serotonergic neurons producing this compound are involved in a broad range of physiological and behavioral processes such as cardiovascular regulation, respiration, thermoregulation, mood, circadian cycles, appetite, pain sensitivity, sexual behavior, cognition and learning. They play important part in a range of psychiatric disorders (anxiety disorders, depression, schizophrenia) as well as less structured behavioral impulse-related disorders (violence, substance abuse, obsessive control, gambling addiction, attention deficit disorder etc.).

Structure and components of serotonergic system

There is only small number of cells in our nervous system that produce serotonin. They are scattered in hindbrain and midbrain. Largely they are present in several regions of the brain called raphe nuclei. There are only around 300,000 serotonin-producing neurons in human brain, but they have an extensive system of connections which has huge number of branches. As a result, serotonergic system reaches almost all areas of central nervous system.

Serotonergic system is one of the evolutionary oldest and seems to be involved in various inhibitory responses throughout the central nervous system. It opposes most of other brain regulatory systems in terms of behavioral and sensory output.

Serotonin production and sensitivity is regulated by multiple cellular mechanisms

The outcome of the serotonin release by the nervous cell depends on the type of receptor it binds to on the target cell. Receptor is needed to convey the signal of serotonin to the cell. Depending on the receptor type, the result of signalling can be quite different. At least 17 types of receptors responding to serotonin were discovered so far. They are located on different cell and can be involved in very different functions. Some of the most studied receptors are 5-HT 1A-1D, 5-HT 2 and 5-HT 3.

Lots of proteins and enzymes are involved in the metabolism and re-utilization of serotonin and can influence its level. Mutations and defects in corresponding genes affect the levels of serotonin or sensitivity to serotonin and may cause behavioral changes.

A specific protein called Serotonin Transporter (SERT) is responsible for bringing serotonin back to the cell that released it. This protein is targeted by a number of psychoactive drugs (psychostimulants and antidepressants) that slow down the transport activity and thus inhibit the re-uptake of the neurotransmitter.

The enzyme called MAO-A (monoaminooxidase A) converts serotonin into inactive molecules. Inhibition of this enzyme leads to accumulation of serotonin and has positive effect in releasing the symptoms caused by lowered concentration of serotonin.

Changes In Behavior Can Be Caused By Changes In Serotonin Level

Alterations of the genes encoding the above mentioned proteins and receptors result in the changes of the levels of serotonin and cause various behavioral changes.

Defects of 5-HT 1A receptors lead to the increase in anxiety. The decrease of the level of serotonin generated by the action of monoaminooxidase A was associated with violent behavior and antisocial personality disorder. Increased level of serotonin in early life, associated with decreased activity of monoaminooxidase A, seems to be correlating with the higher risk of violent behavior and aggression in the adulthood.

Abnormalities in serotonin signalling are important in development of schizophrenia (this is so-called serotonin hypothesis of schizophrenia). Drugs that can block 5-HT 2A serotonin receptors are effective for schizophrenia.

Various compounds capable of binding to serotonin receptors induce a variety of behavioral responses. Many drugs are acting via serotonergic system. For instance, the 5-HT 2A receptors seem to be involved in the mechanism of LSD, one of the strongest hallucinogens known. LSD binding with this receptor is an initial event leading to general decrease in inhibitory action of serotonergic system. Certain similarities between the effects of LSD and mystical experience makes some authors to speculate that serotonergic system is also involved in our perception of religious experience.

Connections between serotonergic activity and suicidal behavior

Researchers argue that the suicidal behavior can be connected to other characteristics such as impulsiveness and aggression and some individuals are more vulnerable due to underlying genetic factors. Some scientists estimate that genetic factors play role in 30 – 50% of suicides.

Low serotonergic activity is associated with depressions and suicidal behavior. There are a number of genetic factors leading to decreased level of serotonergic activity in certain areas of the brain. They contribute to the development of various psychopathologies.

Correlation between suicide attempts and decreased level of serotonin in cerebrospinal fluid was reported for patients with major depressions.

Tryptophan hydroxylase is one of the enzymes involved in biosynthesis of serotonin. Several genetic alterations in its gene were reported to be associated with suicidal behavior.

Impulsive aggressive and sexual behavior was well documented in mice lacking 5-HA 1B receptor gene which is similar to the human version. One common human version of this receptor seems to be associated with a history of suicide attempts. The results of these studies are not conclusive though.

Several studies report the connection between suicidal behavior and the elevated level of 5-HT 2A receptor in prefrontal cortex.

We don’t have genes for suicide but some genes are associated with predisposition to depressive and suicidal behavior

There is no single “suicide gene” in human genome, but some genetic mutations and alterations in the genes involved in regulation of serotonergic system certainly create conditions for higher likelihood of deep depressions and suicides. Suicidal behavior, like most of other psychopathological disorders, involves complex gene interaction and can’t be explained by only one single factor. The studies provide clear evidences that suicidal tendencies can be inherited by children from parents, and individuals that are genetically prone would have higher probability of committing suicide if they are faced with adverse life events or suffer from psychopathologies.

Serotonergic system doesn’t seem to have a direct control of anything critical but it participates in the vast variety of behavioral responses and modulates them. As a result, its involvements can be seen in a significant number of complex diseases and conditions such as schizophrenia and depression. The complexity of serotonergic system presents a challenge for developing the drugs targeting its components: in addition to desirable effects various side effects associated with the same drug are usually observed.