Serotonin

Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesised in serotonergic neurons in the central nervous system and enterochromaffin cells in the gastrointestinal tract.

In the central nervous system, serotonin is believed to play an important role in the regulation of mood, sleep, emesis (vomiting), sexuality and appetite. Serotonin has been thought to play a part in many disorders, notably as part of the biochemistry of depression, migraine, bipolar disorder and anxiety.

The name "serotonin" is something of a misnomer and reflects the circumstances of the compound's discovery. It was initially identified as a vasoconstrictor substance in blood serum - hence serotonin, a serum agent affecting vascular tone. This agent was later chemically identified as 5-hydroxytryptamine (5-HT), and, as the broad range of physiological roles were elucidated, 5-HT became the preferred name in the pharmacological field.

Biochemistry
Serotonin is found extensively in the human gastrointestinal tract, or gut, as well as in the blood stream.

In the body, serotonin is synthesized from the amino acid tryptophan by short metabolic pathway consisting of two enzymes - TPH(1,2) and DDC. TPH1 reaction controls the flux through the pathway.



Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system because it does not cross the blood-brain barrier. However, the amino acid tryptophan and its metabolite 5-hydroxytryptophan, from which serotonin is synthesized, can and do cross the blood-brain barrier. These agents are available as dietary supplements and may be effective serotonergic agents.

One breakdown product of serotonin is 5-hydroxyindoleacetic acid (5 HIAA) which is excreted in the urine. Serotonin and 5HIAA are sometimes produced in excess amounts by certain cancer tumors, and levels of these substances may be measured in the urine to test for these tumors.

Neurotransmission
The neurons of the Raphe nuclei release 5-HT. These neurons are grouped into about nine pairs, distributed along the entire length of the brainstem. 5-HT is thought to be released from serotonergic varicosities into the extra neuronal space, in other words from swellings (varicosities) along the axon, rather than from synaptic terminal buttons (in the manner of classical neurotransmission). From here it is free to diffuse over a relatively large region of space (>20µm) and activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.

Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the specific monoamine transporter for 5-HT, 5-HT reuptake transporter, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including MDMA, cocaine, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).

Pharmacology
The pharmacology of 5-HT is extremely complex, with its actions being mediated by a large and diverse range of 5-HT receptors.

As with all neurotransmitters, the actual effects of 5-HT on the human mood and state of mind, and its role in consciousness, are very difficult to ascertain.

One way of understanding it is through the use of MDMA, which is thought to cause a mass release of 5-HT, possibly by drawing it back through the transporter.

The effects of MDMA are in large part due to the 5-HT which floods synapses during an MDMA "roll," an experience which typically includes feelings of well-being, comfort, tactile sensitivity, and, at high doses, feelings of emotional empathy or entactogenesis. (MDMA also releases norepinephrine, and to a much lesser extent, dopamine. MDEA, a closely related drug, appears to be purely a serotonin releasing agent, and lacks the strong stimulant effect of MDMA.)

5-HT receptors are also used by other psychoactive drugs, including LSD, DMT, and psilocybin, the active ingredient in psychedelic mushrooms.

Modulating levels of 5-HT
A variety of psychiatric medications affect serotonin levels, including the monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), atypical antipsychotics, and the selective serotonin reuptake inhibitors (SSRIs).

Antidepressants
The MAOIs prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive crisis triggered by foods with high tyramine-content and certain drugs.

Some drugs inhibit this re-uptake of serotonin, again making it stay in the synapse longer. The tricyclic antidepressants inhibit the re-uptake of both serotonin and norepinephrine. The newer Selective Serotonin Re-uptake Inhibitors (SSRIs) have fewer (though still numerous) side effects and fewer interactions with other drugs.

Recent research conducted at Rockefeller University shows that in both patients who suffer from depression and in mice that model that disease, levels of the p11 protein are decreased. This protein is related to serotonin transmission within the brain.

Antiemetics
5-HT3 antagonists such as ondansetron, granisetron and tropisetron are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in treatment of post-operative nausea and vomiting. Applications to the treatment of depression and other mental and psychological conditions have also been investigated with some positive results.

Deficiency
Deficient (and sometimes, excessive) intake of various dietary minerals, drugs, and vitamins can lead to disturbed levels of serotonin via disrupting either the production or reuptake processes.

Serotonin syndrome
Care must be taken in any attempt to increase serotonin levels, as a dangerous condition known as serotonin syndrome may result. This is especially a concern if multiple serotonergic agents interact to increase 5-HT levels - such as can happen when St John's wort is taken in combination with an SSRI.