A hydroxy-group at carbon 5 of the carbon skeleton of L-tryptophan without a carboxyl group gives serotonin its descriptive chemical name, 5-hydroxytryptamine.
Serotonin has broad activities in the brain, and genetic variation in serotonin receptors and the serotonin transporter, which facilitates reuptake of serotonin into presynapses, have been implicated in neurological diseases. Drugs targeting serotonin-induced pathways are being used in the treatment of many psychiatric disorders, and one focus of clinical research is the influence of genetics on serotonin action and metabolism in psychiatric settings. Such studies have revealed that the variation in the promoter region of the serotonin transporter protein accounts for nearly 10% of total variance in anxiety-related personality,[2] and the effect of this gene on depression was found to interact with the environment.[3]
Levels of serotonin in the brain show association with aggression [4], and a mutation in the gene which codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype.[5]
Using the ultimatum game as model, it was shown that people whose serotonin levels have been artificially lowered will reject unfair offers more often than players with normal serotonin levels.[6]
In addition, serotonin is also a peripheral signal mediator. It is found extensively in the human gastrointestinal tract as about 80-90% of the body's total serotonin is found in the enterochromaffin cells in the gut.[7][8] In the blood, the major storage site is platelets, which collect serotonin for use in mediating post-injury vasoconstriction.[9]
Recent research suggests that serotonin plays an important role in liver regeneration and acts as a mitogen (induces cell division) throughout the body. Recent research also suggests that intestinal serotonin may inhibit bone formation. [2][10]
Serotonin and SIDS
Defective signalling of serotonin in the brain may be the root cause of sudden infant death syndrome (SIDS), Italian researchers have found. Scientists from the European Molecular Biology Laboratory in Monterotondo, Italy,[11] genetically modified lab mice to produce low levels of the brain signaling protein serotonin. The results showed the mice suffered drops in heart rate and other symptoms of SIDS, and many of the animals died at an early age.
Researchers now believe that low levels of serotonin in the animals' brainstems, which control heartbeat and breathing, may have caused sudden death, researchers said in the July 4, 2008 issue of Science.[12]
Serotonin and psychology
Serotonin, or 5-hydroxytryptamine (5-HT), has been implicated in almost every conceivable physiologic or behavioral function—affect, aggression, appetite, cognition, emesis,endocrine function, gastrointestinal function, motor function, neurotrophism, perception, sensory function, sex,sleep, and vascular function (1).Moreover, most drugs that are currently used for the treatment of psychiatric disorders(e.g., depression, mania, schizophrenia, autism, obsessivecompulsive disorder, anxiety disorders) are thought to act, at least partially, through serotoninergic mechanisms .How is it possible for 5-HT to be involved in so many different processes? One answer lies in the anatomy of the serotoninergic system, in which 5-HT cell bodies clustered in the brainstem raphe nuclei are positioned through their vast projections to influence all regions of the neuraxis.Another answer lies in the molecular diversity and differential cellular distribution of the many 5-HT receptor subtypes that are expressed in brain and other tissues.
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.
Gross anatomy
The neurons of the raphe nuclei are the principal source of 5-HT release in the brain.[13]
The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the brainstem, centered around the reticular formation. [14]
Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching large areas of the brain. Axons of neurons in the caudaldorsal raphe nucleus terminate in e.g.:
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.
Genetic variations in alleles which code for serotonin receptors are now known to have a significant impact on the likelihood of the appearance of certain psychological disorders and problems. For instance, a mutation in the allele which codes for the 5-HT2A receptor appears to double the risk of suicide for those with that genotype. [3]. However, evidence for this has yet to be replicated satisfactorily, and doubts over the validity of this finding have been raised. It is very unlikely that one individual gene could be responsible for increased suicides. It is more probable that a number of genes combine with environmental factors to affect behaviour in this way.
Recent research suggests that serotonin plays an important role in liver regeneration and acts as a mitogen (induces cell division) throughout the body.[15]
Brain development
Recent experimental data support the role of serotonin in modulating brain development, so that a dysfunction in serotonergic activity in early life could lead to long lasting structural and functional alterations.
It has also been discovered that serial killers consistently have low levels of serotonin. This is possibly a result of the aggressive and angry behaviors also associated with low levels of serotonin).
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.[19]
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, tryptophan and its metabolite5-hydroxytryptophan (5-HTP), 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 product of serotonin breakdown is 5-Hydroxyindoleacetic acid (5 HIAA), which is excreted in the urine. Serotonin and 5 HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors.
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 emergency 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 (TCAs) 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.
Like many centrally active drugs, prolonged use of SSRIs may not be effective for increasing levels of serotonin as homeostasis may reverse the effects of SSRIs via negative feedback, tolerance or downregulation.
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.[20] The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels.[21] For example, recreational doses of MDMA (ecstasy) will generally cause such symptoms but only rarely lead to true toxicity.
Chronic diseases resulting from serotonin 5-HT2B overstimulation
Main article: Cardiac fibrosis
In blood, serotonin stored in platelets is active wherever platelets bind, as a vasoconstictor to stop bleeding, and also as a fibrocyte mitotic, to aid healing. Because of these effects, overdoses of serotonin, or serotonin agonist drugs, may cause acute or chronic pulmonary hypertension from pulmonary vasoconstriction, or else syndromes of retroperitoneal fibrosis or cardiac valve fibrosis (endocardial fibrosis) from overstimulation of serotonic growth receptors on fibrocytes.
Serotonin itself may cause a syndrome of cardiac fibrosis when it is eaten in large quantities in the diet (the Matoki banana of East Africa) or when it is over-secreted by certain mid-gut carcinoid tumors. The valvular fibrosis in such cases is typically on the right side of the heart, since excess serotonin in the serum outside platelets is metabolized in the lungs, and does not reach the left circulation.
Serotonergic agonist drugs in overdose in experimental animals not only cause acute (and sometimes fatal) pulmonary hypertension, but there is epidemiologic evidence that chronic use of certain of these drugs produce a chronic pulmonary hypertensive syndrome in humans, also. Some serotinergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as right-sided cardiac valve fibrosis.
In the past, three groups of serotonergic drugs have been epidemiolgically linked with these syndromes. They are the serotonergic vasoconstrictive anti-migraine drugs (ergotamine and methysergide), the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include (pergolide and cabergoline, but not the more specific lisuride). A number of these drugs have recently been withdrawn from the market after groups taking them showed a statistical increase of one or more off the side effects described.
Because neither the amino acid L-tryptophan nor the SSRI-class antidepressants raise blood serotonin levels, they are not under suspicion to cause the syndromes described. However, since 5-hydroxytryptophan (5-HTP) does raise blood serotonin levels, it is under some of the same scrutiny as actively serotonergic drugs.
In unicellular organisms
Serotonin is used by a variety of single-cell organisms for various purposes. Selective serotonin re-uptake inhibitors (SSRIs) have been found to be toxic to algae.[22] The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients.[23][24] Patients infected with Entamoeba histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.[25]Entamoeba histolytica also responds to the presence of serotonin by becoming more virulent.[26]
In animals
Serotonin as a neurotransmitter is found in all animals, including insects. Several toad venoms, as well as that of the Brazilian Wandering Spider and stingray, contain serotonin and related tryptamines.
History
Isolated and named in 1948 by Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic,[27] 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) by Rapport, and, as the broad range of physiological roles were elucidated, 5-HT became the preferred name in the pharmacological field.
See also
5-HTP a serotonin precursor found in food and often sold as a supplement.
↑ Lesch, K.; Bengel, D.; Heils, A.; Sabol, S. Z.; Greenberg, B. D.; Petri, S.; Clemens, R.; Müller, J. B.; Hamer, D. H.; Murphy, D. L. (1996). Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region. Science274: 1527–31.
↑Caspi, A.; Sugden, K.; Moffitt, T. E.; Taylor, A.; Craig, I. W.; Harrington, W.; McClay, J.; Mill, J.; Martin, J.; Braithwaite, A.; Poulton, R. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science301: 386–89.
↑ Caspi N, Modai I, Barak P, Waisbourd A, Zbarsky H, Hirschmann S, Ritsner M. (2001 Mar). Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study. Int Clin Psychopharmacol.16(2): 111-5.
↑Crockett, M. J.; Clark, L.; Tabibnia, G.; Lieberman, M. D.; Robbins, T. W. (June 2008). Serotonin modulates behavioral reactions to unfairness. Science (journal)320 (5884).
↑Lesurtel M. et al (2006). Platelet-derived serotonin mediates liver regeneration. Science312 (5770): 104–7. PMID 16601191.
↑Paterson D.S. et al (2006). Multiple Serotonergic Brainstem Abnormalities in Sudden Infant Death Syndrome. Journal of the American Medical Association296: 2124–2132.
↑Lars Farde & Jacqueline Borg, section of psychiatry at Karolinska Institutet in Stockholm, Sweden 2003, the study and a vulgarized article
↑Svenningsson P, et al (2006). Alterations in 5-HT1B receptor function by p11 in depression-like states. Science311 (5757): 77–80. PMID 16400147.
↑Isbister, G.K., et al., Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. Journal of Toxicology. Clinical Toxicology, 2004. 42(3): p. 277-85.
↑Dunkley, E.J.C., et al., Hunter Serotonin Toxicity Criteria: a simple and accurate diagnostic decision rule for serotonin toxicity. Quarterly Journal of Medicine, 2003. 96: p. 635-642.
↑Johnson DJ, Sanderson H, Brain RA, Wilson CJ, Solomon KR (2007). Toxicity and hazard of selective serotonin reuptake inhibitor antidepressants fluoxetine, fluvoxamine, and sertraline to algae. Ecotoxicol. Environ. Saf.67 (1): 128-39.
↑McGowan K, Kane A, Asarkof N, et al (1983). Entamoeba histolytica causes intestinal secretion: role of serotonin. Science221 (4612): 762-4.
↑McGowan K, Guerina V, Wicks J, Donowitz M (1985). Secretory hormones of Entamoeba histolytica. Ciba Found. Symp.112: 139-54.
↑Acharya DP, Sen MR, Sen PC (1989). Effect of exogenous 5-hydroxytryptamine on pathogenicity of Entamoeba histolytica in experimental animals. Indian J. Exp. Biol.27 (8): 718-20.
↑Rapport MM, Green AA, Page IH (1948). "Serum vasoconstrictor (serotonin). IV. Isolation and characterization". J Biol Chem '176' (3): 1243–1251.
Key texts
Books
Papers
Aghajanian, GK, Sanders-Bush, E. Serotonin. Fulltext
Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, Yacoubi ME, Vaugeois JM, Nomikos GG, Greengard P. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 2006;311(5757):77–80. PMID 16400147
Barbas, D., DesGroseillers, L., Castellucci, V.F., Carew, T.J., & Marinesco, S. (2003). Multiple Serotonergic Mechanisms Contributing to Sensitization in Aplysia: Evidence of Diverse Serotonin Receptor Subtypes. Learning & Memory, 10, 373 - 386. Full text
Burrell, B.D. & Sahley, C.L. (1999). Serotonin Depletion Does Not Prevent Intrinsic Sensitization in the Leech. Learning & Memory, 6, 509 - 520. Full text
