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Biochemistry
Neurotransmission The neurons of the Raphe nuclei are the principal source of 5-HT release.• 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 (ecstasy), cocaine, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Recent research suggests that serotonin plays an important role in liver regeneration and acts as a mitogen (induces cell division) throughout the body.• Pharmacology The pharmacology of 5-HT is extremely complex, with its actions being mediated by a large and diverse range of 5-HT receptors. At least seven different receptor "families" are known to exist, each located in different parts of the body and triggering different responses. As with all neurotransmitters, the 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 (ecstasy), which is thought to cause a massive release of 5-HT, possibly by drawing it back through the transporter. The distinctive emotional effects of MDMA are caused by 5-HT flooding synapses during an MDMA use, 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.) MDMA has also been shown to alleviate the symptoms of Parkinson's Disease, though this effect is thought to be mediated by its secondary effects on dopamine release, rather than serotonin itself. 5-HT receptors are also used by other psychoactive drugs, including LSD, DMT, and psilocybin, the active ingredient in psychedelic mushrooms. Modulating levels 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. Serotonin syndrome Extremely high levels of serotonin can have toxic and potentially fatal effects, causing a condition known as serotonin syndrome. In practice, such toxic levels are essentially impossible to reach through an overdose of a single anti-depressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI. The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels. For example, recreational doses of MDMA will generally cause such symptoms but only rarely lead to true toxicity. See also | ||||||||||||||||||||||||||||||
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