| Formula = </sub>C<sub>10</sub>H<sub>12</sub>N<sub>2</sub>O<sub>
+
| MolarMass = 176.215
+
| Appearance =
+
| Density =
+
| MeltingPt =
+
| BoilingPt =
+
}}
+
| Section3 = {{Chembox Hazards
+
| Solubility =
+
| MainHazards =
+
| FlashPt =
+
| Autoignition =
+
}}
+
}}
+
'''Serotonin''' ({{pronEng|ˌsɛrəˈtoʊnən}}) ('''5-hydroxytryptamine''', or '''5-HT''') is a [[monoamine]] [[neurotransmitter]] synthesized in serotonergic [[neuron]]s in the [[central nervous system]] (CNS) and [[enterochromaffin cell]]s in the [[gastrointestinal tract]] of [[animals]] including [[humans]]. Serotonin is also found in many mushrooms and plants, including fruits and vegetables.
[[File:5-HT numbered.svg|thumb|left|200px|A hydroxy-group at carbon 5 of the carbon skeleton of <small>L</small>-tryptophan without a [[carboxyl group]] gives serotonin its descriptive chemical name, ''5-hydroxytryptamine''.]]
+
In the [[central nervous system]], serotonin plays an important role as a [[neurotransmitter]] in the modulation of [[anger]], [[aggression]], [[Thermoregulation|body temperature]], [[Mood (psychology)|mood]], [[sleep]], [[human sexuality]], [[appetite]], and [[metabolism]], as well as stimulating [[vomiting]].<ref>[http://drugs.emedtv.com/dolasetron/dolasetron.html Dolasetron<!-- Bot generated title -->]</ref>
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,<ref> {{Cite journal | author = 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. | title = Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region | journal = [[Science]] | year = 1996 | volume = 274 | pages = 1527–31 | doi = 10.1126/science.274.5292.1527 | pmid = 8929413}}</ref> and the effect of this gene on [[Major depressive disorder|depression]] was found to interact with the environment.<ref>{{Cite journal | author = Caspi, A.; Sugden, K.; Moffitt, T. E.; Taylor, A.; Craig, I. W.; Harrington, W.; McClay, J.; Mill, J.; Martin, J.; Braithwaite, A.; Poulton, R. | title = Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene | journal = [[Science]] | year = 2003 | volume = 301 | pages = 386–89 | doi = 10.1126/science.1083968 | pmid = 12869766}}</ref>
Levels of serotonin in the brain show association with aggression <ref> {{Cite journal | author = Caspi N, Modai I, Barak P, Waisbourd A, Zbarsky H, Hirschmann S, Ritsner M. | title = Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study | journal = Int Clin Psychopharmacol. | year = 2001 Mar | volume = 16(2) | pages = 111-5 | doi = | pmid = 11236069}}</ref>, and a mutation in the gene which codes for the [[5-HT2A receptor|5-HT<sub>2A</sub>]] receptor may double the risk of suicide for those with that genotype.<ref>{{Cite journal
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.<ref>{{Cite journal
|author=Crockett, M. J.; Clark, L.; Tabibnia, G.; Lieberman, M. D.; Robbins, T. W. |title=Serotonin modulates behavioral reactions to unfairness |journal=Science (journal) |volume=320 |issue=5884 |page=1739 |year=2008 |month=June |pmid=18535210 |pmc=2504725 |doi=10.1126/science.1155577
+
}}</ref>
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In addition, serotonin is also a [[Periphery|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.<ref>[http://web.indstate.edu/thcme/mwking/nerves.html Indiana State University]</ref><ref>[http://www.clinlabnavigator.com/Tests/Serotonin.html] Serotonin tests info, Accessed May 6, 2008</ref> In the blood, the major storage site is [[platelet]]s, which collect serotonin for use in mediating post-injury [[vasoconstriction]].<ref>''Essentials of Human Anatomy & Physiology'', Eighth Edition, p. 336</ref>
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. [http://www.sciencedaily.com/releases/2008/11/081126122209.htm] <ref>Cell 135, 825–837, November 28, 2008</ref>
<tr><td>[[Simplified molecular input line entry specification|SMILES]]</td><td>NCCC1=CNC2=C1C=C(O)C=C2</td></tr>
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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,<ref> {{Cite journal | author = Audero, Enrica; Coppi, Elisabetta; Mlinar, Boris; Rossetti, Tiziana; Caprioli, Antonio; Al Banchaabouchi, Mumna; Corradetti, Renato; Gross, Cornelius | title = Sporadic Autonomic Dysregulation and Death Associated with Excessive Serotonin Autoinhibition | journal = [[Science]] | year = 2008 | volume = 321 | pages = 130–133 | doi = 10.1126/science.1157871 | pmid = 18599790}}</ref> 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.
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<tr><td colspan="2" align="center">[[Image:Serotonin.png|chemical structure of serotonin]]<br>[[Image:Serotonin.gif|3D structure of serotonin]]</td></tr>
−
</table>
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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.<ref>{{cite journal
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'''Serotonin''' ('''5-hydroxytryptamine''', or '''5-HT''') is a [[monoamine]] [[neurotransmitter]] synthesised in serotonergic [[neuron]]s in the [[central nervous system]] and [[enterochromaffin]] [[cell (biology)|cell]]s in the [[gastrointestinal tract]].
+
| author = Lesurtel, M. ''et al.''
+
| year = 2006
+
| title = Platelet-derived serotonin mediates liver regeneration
+
| journal = [[Science (journal)|Science]]
+
| volume = 312
+
| issue = 5770
+
| pages = 104–7
+
| pmid = 16601191
+
| doi = 10.1126/science.1123842
+
}}</ref>
+
==Serotonin and psychology==
−
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 [[Clinical depression|depression]], [[migraine]], [[bipolar disorder]] and [[anxiety]].
+
<Blockquote>Serotonin, or 5-hydroxytryptamine (5-HT), has been implicated in almost every conceivable physiologic or behavioral function—[[Affect and serotonin|affect]], [[Aggression and serotonin|aggression]], [[Appetite and serotonin|appetite]], [[Cognition and serotonin|cognition]], [[emesis]],[[endocrine function]], gastrointestinal function, motor function, [[neurotrophism]], [[Perception and serotonin|perception]], [[Sensory function and serotonin|sensory function]], [[Sex and serotonin|sex]],[[Sleep and serotonin|sleep]], and vascular function (1).Moreover, most drugs that are currently used for the treatment of psychiatric disorders(e.g., [[Depression and serotonin|depression]], [[Bipolar disorder and serotonin|mania]], [[Schizophrenia and serotonin|schizophrenia]], [[Autism and serotonin|autism]], [[OCD and serotonin|obsessivecompulsive disorder]], [[Anxiety and serotonin|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.<Blockquote/>
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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.
+
*[[SAD - Serotonin]]
−
==Biochemistry==
+
*[[Clinical depression - Serotonin]]
−
Serotonin is found extensively in the human [[gastrointestinal tract]], or gut, as well as in the blood stream.
+
*[[Schizophrenia - Serotonin]]
+
*[[Bipolar disorder - Serotonin]]
+
*[[Autism - Serotonin]]
+
*[[OCD - Serotonin]]
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In the body, serotonin is synthesized from the [[amino acid]] [[tryptophan]] by short [[metabolic pathway]] consisting of two [[enzyme]]s - TPH([[Tryptophan hydroxylase 1|1]],[[Tryptophan hydroxylase 2|2]]) and [[Aromatic-L-amino-acid decarboxylase|DDC]]. TPH1 [[reaction]] controls the flux through the pathway.
−
<br />
+
=== Neurotransmission ===
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[[image:5htsynt_2.png|frame|left|403px|The pathway for the synthesis of serotonin from Trp]]<br style="clear: both;" />
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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.
−
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-HTP|5-hydroxytryptophan]], from which serotonin is synthesized, can and do cross the blood-brain barrier. These agents are available as [[dietary supplement]]s and may be effective serotonergic agents.
+
==== Gross anatomy ====
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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|cancer tumors]], and levels of these substances may be measured in the urine to test for these tumors.
+
The neurons of the [[raphe nuclei]] are the principal source of 5-HT release in the brain.<ref>{{cite book
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==Neurotransmission==
+
| editor = George J. Siegel
+
| others = Bernard W. Agranoff, Stephen K. Fisher, R. Wayne Albers, Michael D. Uhler
| chapter = Understanding the neuroanatomical organization of serotonergic cells in the brain provides insight into the functions of this neurotransmitter
| quote = In 1964, Dahlstrom and Fuxe (discussed in [2]), using the Falck-Hillarp technique of histofluorescence, observed that the majority of serotonergic soma are found in cell body groups, which previously had been designated as the raphe nuclei.
+
}}</ref>
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The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the [[brainstem]], centered around the [[reticular formation]]. <ref>|The [[Raphe nuclei]] group of [[neurons]] are located along the [[reticular formation|brain stem]] from the labels '[[mesencephalon|Mid Brain]]' to '[[medulla oblongata|Oblongata]]', centered on the [[pons]]. ([[:Image:Gray715.png|See relevant image]].)</ref>
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Axons from the neurons of the raphe nuclei form a [[neurotransmitter system]], reaching large areas of the brain. Axons of neurons in the ''caudal'' [[dorsal raphe nucleus]] terminate in e.g.:
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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 receptor]]s located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.
+
* [[Deep cerebellar nuclei]]
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Serotonergic action is terminated primarily via [[reuptake|uptake]] of 5-HT from the synapse. This is through the specific [[monoamine transporter]] for 5-HT, [[Serotonin transporter|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 inhibitor]]s (SSRIs).
+
* [[Cerebellar cortex]]
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* [[Spinal cord]]
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On the other hand, axons of neurons in the ''rostral'' [[dorsal raphe nucleus]] terminate in e.g.:
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==Pharmacology==
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<div style="column-count: 3;">
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* [[Thalamus]]
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The pharmacology of 5-HT is extremely complex, with its actions being mediated by a large and diverse range of [[5-HT receptors]].
+
* [[Striatum]]
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* [[Hypothalamus]]
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* [[Nucleus accumbens]]
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* [[Neocortex]]
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* [[Cingulate gyrus]]
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* [[Cingulum]]
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* [[Hippocampus]]
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* [[Amygdala]]</div>
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Thus, activation of this serotonin system has effects on large areas of the brain, which explains the effects of therapeutic modulation of it.
−
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.
+
{{Serotonin}}
+
==== Microanatomy ====
+
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 receptor]]s located on the [[dendrite]]s, cell bodies and [[presynaptic terminal]]s of adjacent neurons.
−
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.
+
===== Receptors =====
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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.)
+
{{main|5-HT receptor}}
+
[[5-HT receptor]]s are the [[receptor (biochemistry)|receptors]] for serotonin. They are located on the cell membrane of [[Neuron|nerve cells]] and other cell types in animals and mediate the effects of serotonin as the [[endogenous]] [[ligand]] and of a broad range of pharmaceutical and [[Psychedelics, dissociatives and deliriants|hallucinogenic drugs]]. With the exception of the [[5-HT3|5-HT<sub>3</sub> receptor]], a ligand gated [[ion channel]], all other 5-HT receptors are [[G-protein-coupled receptor|G protein coupled seven transmembrane]] (or ''heptahelical'') receptors that activate an [[intracellular]] [[second messenger]] cascade.
−
5-HT receptors are also used by other psychoactive drugs, including [[LSD]], [[Dimethyltryptamine|DMT]], and [[psilocybin]], the active ingredient in [[psychedelic mushrooms]].
+
===== Genetic factors =====
−
==Modulating levels of 5-HT==
+
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|5-HT<sub>2A</sub>]] receptor appears to double the risk of suicide for those with that genotype. [http://www.cmaj.ca/cgi/content/full/162/9/1343-a]. 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.
−
A variety of [[psychiatric medication]]s affect serotonin levels, including the [[monoamine oxidase inhibitors]] (MAOIs), [[tricyclic antidepressants]] (TCAs), [[atypical antipsychotic]]s, and the [[selective serotonin reuptake inhibitor]]s (SSRIs).
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===Antidepressants===
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===== Termination =====
−
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.
+
Serotonergic action is terminated primarily via [[reuptake|uptake]] of 5-HT from the synapse. This is through the specific [[monoamine transporter]] for 5-HT, [[Serotonin transporter|5-HT reuptake transporter]], on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including [[MDMA]] (ecstasy), [[amphetamine]], [[cocaine]], [[dextromethorphan]] (an [[antitussive]]), [[tricyclic antidepressants]] (TCAs) and [[selective serotonin reuptake inhibitor]]s (SSRIs).
−
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.
+
=== Other functions ===
−
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{{an|Svenningsson}}.
+
Recent research suggests that serotonin plays an important role in [[liver]] regeneration and acts as a [[mitogen]] (induces cell division) throughout the body.<ref>{{cite journal
−
===Antiemetics===
+
| author = Lesurtel M. et al
−
5-HT<sub>3</sub> [[Receptor antagonist|antagonist]]s 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.
+
| year = 2006
+
| title = Platelet-derived serotonin mediates liver regeneration
+
| journal = [[Science (journal)|Science]]
+
| volume = 312
+
| issue = 5770
+
| pages = 104–7
+
| id = PMID 16601191
+
}}</ref>
+
==Brain development=
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===Deficiency===
+
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.
−
Deficient (and sometimes, excessive) intake of various [[dietary minerals]], [[drugs]], and [[vitamin]]s 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 [[interaction|interact]] to increase 5-HT levels - such as can happen when [[St John's wort]] is taken in combination with an SSRI.
−
== References ==
+
== Pathology ==
+
If neurons of the brainstem that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of [[sudden infant death syndrome]] (SIDS).<ref name="SIDS">{{cite journal
−
* Rang HP, Dale MM, Ritter JM, Moore PK (2003). ''Pharmacology'' (5 ed). Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4
+
| author = Paterson D.S. et al
−
#{{anb|Svenningsson}} 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
+
| year = 2006
+
| title = Multiple Serotonergic Brainstem Abnormalities in Sudden Infant Death Syndrome
+
| journal = Journal of the American Medical Association
+
| volume = 296
+
| number = 17
+
| pages = 2124–2132
+
}}</ref><ref>[http://www.sciencedaily.com/releases/2007/03/070309103136.htm Sciencedaily Report ''Anger and Aggression in Women: Blame It On Genetics'']</ref> Low levels of serotonin may also be associated with [[Relationship between religion and science#Scientific study of religion|intense religious experiences]].<ref>Lars Farde & Jacqueline Borg, section of psychiatry at Karolinska Institutet in Stockholm, Sweden 2003, [http://ajp.psychiatryonline.org/cgi/content/full/160/11/1965? the study] and a [http://www.beliefnet.com/story/140/story_14076_1.html vulgarized article]</ref>
+
+
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.<ref>{{cite journal
+
| author = Svenningsson P, et al
+
| year = 2006
+
| title = Alterations in 5-HT1B receptor function by p11 in depression-like states
+
| journal = Science
+
| volume = 311
+
| issue = 5757
+
| pages = 77–80
+
| id = PMID 16400147
+
}}</ref>
+
+
== Synthesis ==
+
+
[[Image:Serotonin biosynthesis.svg|thumb|right|400px|The pathway for the synthesis of serotonin from tryptophan]]
+
+
In the body, serotonin is synthesized from the [[amino acid]] [[tryptophan]] by a short [[metabolic pathway]] consisting of two [[enzyme]]s: [[tryptophan hydroxylase]] (TPH) and [[Aromatic L-amino acid decarboxylase|amino acid decarboxylase]] (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several [[Biological tissue|tissues]], and TPH2, which is a brain-specific [[Protein isoform|isoform]]. There is evidence that [[polymorphism (biology)|genetic polymorphisms]] in both these subtypes influence susceptibility to anxiety and depression. There is also evidence that [[ovarian hormones]] can affect the expression of TPH in various species, suggesting a possible mechanism for [[postpartum depression]] and [[premenstrual stress syndrome]].
+
+
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 [[metabolite]] [[5-hydroxytryptophan]] (5-HTP), from which serotonin is synthesized, can and do cross the blood-brain barrier. These agents are available as [[dietary supplement]]s 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 [[tumor]]s or [[cancer]]s, and levels of these substances may be measured in the urine to test for these tumors.
+
+
== Serotonergic drugs ==
+
+
Several classes of [[drugs]] target the 5-HT system including some [[antidepressant]]s, [[antipsychotic]]s, [[anxiolytic]]s, [[antiemetic]]s, and [[migraine|antimigraine drugs]] as well as the [[psychoactive drugs]] [[psychedelic drug]]s and [[empathogen]]s.
+
+
== Psychoactive drugs ==
+
+
The [[psychedelic drug]]s [[psilocin]]/[[psilocybin]], [[dimethyltryptamine|DMT]], [[mescaline]], and [[LSD]] mimick the action of serotonin at [[5-HT2A receptor|5-HT<sub>2A</sub> receptors]]. The [[empathogen]] [[MDMA]] (ecstasy) releases serotonin from [[synaptic]] vesicles of [[neuron]]s.
+
+
=== Antidepressants ===
+
+
The [[MAOI]]s prevent the breakdown of [[monoamine neurotransmitter]]s (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 and non-selective|selective]] serotonin re-uptake inhibitors ([[SSRI]]s) have fewer (though still numerous) side-effects and fewer interactions with other drugs.
+
+
Like many [[central nervous system|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, [[drug tolerance|tolerance]] or [[downregulation]].
+
+
=== Antiemetics ===
+
+
[[5-HT3 antagonist|5-HT<sub>3</sub> antagonist]]s 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]].<ref>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.</ref> The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels.<ref>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.</ref> 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-HT<sub>2B</sub> overstimulation ===
+
{{main|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 fibrosis|cardiac valve fibrosis]].
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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-HT<sub>2B</sub> 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.
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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.
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== In unicellular organisms ==
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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.<ref>{{cite journal |author=Johnson DJ, Sanderson H, Brain RA, Wilson CJ, Solomon KR |title=Toxicity and hazard of selective serotonin reuptake inhibitor antidepressants fluoxetine, fluvoxamine, and sertraline to algae |journal=Ecotoxicol. Environ. Saf. |volume=67 |issue=1 |pages=128-39 |year=2007 |pmid=16753215 |doi=10.1016/j.ecoenv.2006.03.016}}</ref> The gastrointestinal parasite ''[[Entamoeba histolytica]]'' secretes serotonin, causing a sustained secretory diarrhea in some patients.<ref>{{cite journal |author=McGowan K, Kane A, Asarkof N, ''et al'' |title=Entamoeba histolytica causes intestinal secretion: role of serotonin |journal=Science |volume=221 |issue=4612 |pages=762-4 |year=1983 |pmid=6308760 |doi=}}</ref><ref>{{cite journal |author=McGowan K, Guerina V, Wicks J, Donowitz M |title=Secretory hormones of Entamoeba histolytica |journal=Ciba Found. Symp. |volume=112 |issue= |pages=139-54 |year=1985 |pmid=2861068 |doi=}}</ref> Patients infected with ''[[Entamoeba histolytica]]'' have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.<ref>{{cite journal |author=Banu, Naheed, et al. |title=Neurohumoral alterations and their role in amoebiasis. |journal=Indian J. Clin Biochem |volume=20 |issue=2 |pages=142-5 |year=2005 |url=http://medind.nic.in/iaf/t05/i2/iaft05i2p142.pdf}}</ref>''[[Entamoeba histolytica]]'' also responds to the presence of serotonin by becoming more virulent.<ref>{{cite journal |author=Acharya DP, Sen MR, Sen PC |title=Effect of exogenous 5-hydroxytryptamine on pathogenicity of Entamoeba histolytica in experimental animals |journal=Indian J. Exp. Biol. |volume=27 |issue=8 |pages=718-20 |year=1989 |pmid=2561282 |doi=}}</ref>
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== In animals ==
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Serotonin as a [[neurotransmitter]] is found in all animals, including insects. Several [[bufo alvarius|toad venom]]s, as well as that of the Brazilian Wandering Spider and [[stingray]], contain serotonin and related tryptamines.
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== History ==
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Isolated and named in 1948 by Maurice M. Rapport, Arda Green, and [[Irvine Page]] of the [[Cleveland Clinic]],<ref>Rapport MM, Green AA, Page IH (1948). "Serum vasoconstrictor (serotonin). IV. Isolation and characterization". ''J Biol Chem '176''' (3): 1243–1251.</ref> 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 plasma|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.
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== See also ==
== See also ==
* [[5-HTP]] a serotonin precursor found in food and often sold as a supplement.
* [[5-HTP]] a serotonin precursor found in food and often sold as a supplement.
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* [[Adrenergic drugs]]
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* [[Neuromodulation]]
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* [[Serotonin agonists]]
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* [[Serotonin antagonists]]
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* [[Serotonin metabolites]]
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* [[Serotonin precursors]]
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* [[Serotonin syndrome]]
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* [[Serotonin-dopamine reuptake inhibitor]]
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* [[Tryptamine]]
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==References & Bibliography==
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==Key texts==
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===Books===
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===Papers===
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*Aghajanian, GK, Sanders-Bush, E. Serotonin. [http://www.acnp.org/Docs/G5/CH2_15-34.pdf Fulltext]
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*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
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==Additional material==
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===Books===
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===Papers===
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*[http://scholar.google.com/scholar?sourceid=mozclient&num=50&scoring=d&ie=utf-8&oe=utf-8&q=Depression+women Google Scholar]
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* 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. [http://www.learnmem.org/cgi/reprint/10/5/373.pdf Full text]
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* Burrell, B.D. & Sahley, C.L. (1999). Serotonin Depletion Does Not Prevent Intrinsic Sensitization in the Leech. ''Learning & Memory, 6,'' 509 - 520. [http://www.learnmem.org/cgi/reprint/6/5/509.pdf Full text]
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. [1][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. [2]. 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.
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
↑ 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.
