Serotonin is produced in the Pineal gland, located in the centre of the human brain. Serotonin produced in the Pineal gland is stored and released by dense bodies of neurons, called Raphe Nuclei within the medulla, pons and midbrain. These serotonergic neurons have axons that project to many parts of the brain, and it is believed serotonin’s diverse behavioural effects are a consequence of this physical feature.
Figure 1: Broad dispersion of Serotonin from raphe nuclei in the brain
during a panic attack.
DSM-IV-TR definition!
There are many illnesses that are believed to be related to low levels of serotonin. Amongst serotonin related illnesses, depression is by far the most prevalent of serotonin related illness in North America. Depression is characterized by a mixture of symptoms including of sadness, worthlessness, loss of interest or motivation, insomnia that occurs chronically within an individual. It is estimated to affect 12-17% of the population at some point during the lifetime of an individual. (Malberg, 2000)
Depression is believed to be caused by serotonin deficiency in the body. Though this pathology has been studied extensively, there has yet to be a biological mechanism described for depression and the complexity of the human mind may not be a function of biological factors alone. Researchers have measured decreased concentrations of serotonin metabolites in the cerebrospinal fluid and brain tissues of depressed people, and this serves as the most concrete evidence relating depression to serotonin.
To combat depression, antidepressants function to raise the level of serotonin within in synapse.
There are many types of antidepressants available on the market, and they can be grouped based on their mode of action. (Healy, 1997)
The three most common classes of antidepressants are 
- Tricyclic Antidepressants
- Monoamine Oxidase Inhibitors (MAOIs), and
- 5-HT Reuptake Inhibitors (Also known as Selective Serotonin Reuptake Inhibitors, SSRIs) {Most commonly prescribed (eg: Prozac)}. (Healy, 1997)
1 Tricyclic Antidepressants
These compounds have a three-ring (tricyclic) central structure, and serve more so as a sedative rather than a stimulant. First type of antidepressants “discovered” (imipramine, Tofranil), interest in the compound as an antihistamine. (Healy, 1997) This class of compounds are usually secondarily prescribed in cases where SSRI have not served as a successful treatment of depression, because motality due to tricyclic antidepression overdose is a well recognized problem (Barbey 1998).
Figure 2: Chemical structure of the Tricyclic Antidepressant, Imipramine
2 Monoamine Oxidase Inhibitors (MAOIs):
This class of Antidepressants work to increase the levels of serotonin in the synaptic clefts by inhibiting the enzyme monoamine oxidase. Monoamine oxidase, along with the enzyme catchecol-O-methyl transferase are located in the synaptic cleft, and function to degrade serotonin after its release from the presynaptic cell.
Figure 3: Serotonin is released from presynaptic cell vessicles into the synaptic cleft, where they are eventually removed by reuptake and degredation by enzymes such as monoamine oxidase.
The discovery of monoamine oxidase inhibitors is a complex and important story. The first reported MOAI was isoniazid and iproniazid synthesized in 1912, but isoniazids resynthesis in 1951 is of much interest. During WWII, V2 rockets were initially propelled using liquid oxygen and ethanol. Nearing the end of the war, as stocks of these compounds decreased, the rockets were propelled by a compound called hydrazine. When the war ended, production companies found themselves holding a surplus of hydrazine, and these were taken over by chemical companies, many of which who were in the process of developing new pharmaceutical compounds. A series of hydrazine derivatives were formed, one including iproniazid in 1951, and it was found to be an effective anti-tuberculous drug. Physicians, however noticed mental side effect in their tuberculosis patients, including a generally favourable affect on patient demeanor. Newspapers reported patients to be dancing in the wards, regardless of the holes (lesions) in their lungs, and from then on, interest in MOAIs skyrocketed. (Healy,1997)
3 Selective Serotonin Reuptake Inhibitors (SSRIs)
Of all the antidepressants described here, SSRIs are by far the most prevalently prescribed to individuals with depression. Not only do they appear to be effective in broad range of individuals, but this class of antidepressants are thought to be safer in overdose (Barbey, 1998). SSRIs have a mode of action of inhibiting the reuptake of serotonin from the synaptic cleft into the presynaptic cell.
Though antidepressants are commonly prescribed for individuals suffering from depression, anxiety and other affective disorders, the cellular and molecular mechanism by which antidepressants give their therapeutic effect is not well understood.
Serotonin and cell differentiation in the hippocampus
In addition to direct inhibition of serotonin reuptake, chronic administration of antidepressants are suspected to have a mode of action affecting cell differentiation within the hippocampus (Malberg, 2000)
The hippocampus is one of the only brain regions to continue cellular reproduction during the lifetime. Clinical research prior to this study showed that stress and depression had effects on the hippocampus, seen by morphological changes such as atrophy and loss of pyramidal neurons (Malberg, 2000). Antidepressants have been shown to ‘undo’ the morphological changes seen in the hippocampus by upregulating the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. BDNF has been shown to promote cellular differentiation as well as cell survival during development in the adult brain (also shown in vitro). Chronic administration of antidepressants has also been shown to block the stress-induced downregulation of BNDF gene expression (Malberg, 2000).
Seasonal Affective Disorder
A mood disorder related to reduced sunlight in the winter months.
DSM-IV-TR definition
In fruitflies, it has been demonstrated that serotonin decreases the sensitivity of the body to light, and chronic exposure to darkness results in decreased serotonin levels in fruit fly brains (Sehgal et al, 2005). Normally, a protein in flies called cryptochrome controls the response of the body’s circadian rhythm to light. Another protein called GSK3bβ has the ability to affect the sequential events leading to the ‘resetting’ of the circadian clock. Serotonin receptor (5-HT1B) binding leads to activation of GSK3bβ, allowing the body circadian rhythm to be reset (Sehgal et al, 2005).
Figure 5: Binding of serotonin to its receptor affects the cascade involved with expression of compounds resetting the body's circadian rhythm.
Further study of serotonin’s relationship with Seasonal Affective Disorder will help increase the etiology and potential treatments for SAD. Currently, those experiencing SAD may choose to take antidepressants, in attempt to raise their serotonin brain levels and alleviate symptoms (Sehgal et al, 2005). Individuals suffering from depression often exhibit symptoms of insomnia and irregular sleep patterns, which are most likely related to serotonin’s contribution in the regulation of circadian rhythm.
-----------------------------------------------------------------------------------
References:
[1] Barbey, J. T., Roose, S. P. (1998). SSRI Safety in Overdose. Journal of Clinical Psychiatry. (59)15:42-28
[2] DSM-IV-TR
[3] Healy, David. (1997). The Antidepressant Era. Cambridge Massachusettes, USA:Harvard University Press
[4] Malberg, J. E et al. (2000). Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus. Journal of Neuroscience, 20(24):9104-9110
[5] Rosling, Claire. Serotonin: A Molecule of Happiness.
Retrieved November 3, 2008, from
http://www.chm.bris.ac.uk/motm/serotonin/home1.htm
[6] University Of Pennsylvania School Of Medicine. “Penn Researchers Determine Role
Of Serotonin In Modulating Circadian Rhythm." ScienceDaily 11 July
2005. 5 November 2008
