Serotonin

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Serotonin
Image:Serotonin-skeletal.png Image:Serotonin-3D-vdW.png
Chemical name	5-Hydroxytryptamine or 3-(2-aminoethyl)-1H-indol-5-ol
Chemical formula	N₂OC₁₀H₁₂
Molecular mass	176.2182 g/mol
Monoisotopic mass	176.0950 g/mol
Composition (weight)	N: 15.8970% O: 9.0793% C: 68.1598% H: 6.8638%
CAS number	50-67-9
SMILES	NCCC1=CNC2=C1C=C(O)C=C2
IUPAC InChI ID	1/C10H12N2O/c11-4-3-7-6-12-10-2-1- 8(13)5-9(7)10/h1-2,5-6,12-13H,3-4,11H2

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

1 Explanation
2 Biochemistry
3 Neurotransmission
4 Pharmacology
5 Receptors
6 Characterized 5-HT receptors
7 Therapeutic modulation
8 Modulating levels
9 References
10 See also
11 External links

[edit] Explanation

In the central nervous system, serotonin is believed to play an important role in the regulation of body temperature, mood, sleep, vomiting, sexuality, and appetite. Low levels of serotonin have been associated with several disorders, notably clinical depression, migraine, irritable bowel syndrome, tinnitus, fibromyalgia, bipolar disorder, and anxiety disorders. If neurons of the brainstem that make serotonin – serotonergic neurons – are abnormal, there is a risk of sudden infant death syndrome (SIDS) in an infant.<ref name=SIDS>Paterson D.S. et al (2006). "Multiple Serotonergic Brainstem Abnormalities in Sudden Infant Death Syndrome". Journal of the American Medical Association 296: 2124–2132.</ref>

Isolated and named in 1948 by Maurice M. Rapport, 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.

[edit] Biochemistry

Serotonin is synthesized extensively in the human gastrointestinal tract (about 90%),^[1] and the major storage place is platelets in the blood stream.

In the body, serotonin is synthesized from the amino acid tryptophan by a short metabolic pathway consisting of two enzymes – tryptophan hydroxylase (TPH) and 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 tissues and TPH2, which is a brain specific isoform. There is evidence that genetic polymorphisms in both these subtypes influence susceptability to anxiety and depression (Nash et al 2005; Zhang et al 2005). There is also evidence that ovarian hormones can effect the expression of TPH in various species, suggesting a possible mechanism for postpartum depression and premenstrual stress syndrome (Hiroi et al 2006). The gut secretes over 95% of the body's serotonin.<ref name="gershon-second-brain">Gershon, Michael D. (1998). The Second Brain. New York, NY: HarperCollins. ISBN 0-06-018252-0</ref>

Image:5htsynt 2.png

The pathway for the synthesis of serotonin from Trp

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 TPH 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 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.

[edit] Neurotransmission

The neurons of the Raphe nuclei are the principal source of 5-HT release in brain.<ref> (1999) “Understanding the neuroanatomical organization of serotonergic cells in brain provides insight into the functions of this neurotransmitter”, George J. Siegel: Basic Neurochemistry, Bernard W. Agranoff, Stephen K. Fisher, R. Wayne Albers, Michael D. Uhler, Sixth, Lippincott Williams and Wilkins. ISBN 0-397-51820-X. “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> The raphe nuclei 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.<ref>Lesurtel M. et al (2006). "Platelet-derived serotonin mediates liver regeneration". Science 312 (5770): 104–7. PMID 16601191.</ref>

[edit] 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.<ref>David Nichols, "Serotonin and MDMA". David Nichols at MAPS.</ref>

[edit] Receptors

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

In the field of neurochemistry, 5-HT receptors are receptors for the neurotransmitter and peripheral signal mediator serotonin, also known as 5-hydroxytryptamine or 5-HT. 5-HT receptors are located on the cell membrane of 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 hallucinogenic drugs. With the exception of the 5-HT₃ receptor, a ligand gated ion channel, all other 5-HT receptors are G protein coupled seven transmembrane (or heptahelical) receptors that activate an intracellular second messenger cascade.

5-HT₁ receptors are G_i/G_o coupled, mediating cellular effects through decreasing cellular levels of cyclic adenosine monophosphate (cAMP).

5-HT₂ receptors are G_q/G₁₁ coupled, mediating cellular effects through increasing cellular levels of inositol trisphosphate (IP₃) and diacylglycerol (DAG). Three subtypes exist, namely 5-HT_2A, 5-HT_2B, and 5-HT_2C (formerly called 5-HT_1C).

The 5-HT₃ receptor is a ligand-gated Na⁺ and K⁺ cation channel, resulting in a direct plasma membrane depolarization.

The 5-HT₄ receptor is G_s coupled, mediating cellular effects through increasing cellular levels of cAMP.

The 5-HT_5A receptor is G protein coupled; the primary coupling appears to be through Gi/o, inhibiting adenylate cyclase activity.<ref name="Nelson">D.L. Nelson (2004). "5-HT5 receptors". Curr. Drug Targets CNS Neurol. Disord. 3 (1): 53-58. PMID 14965244.</ref> The 5-HT_5B subtype exists, but has not been detected in humans.

The 5-HT₇ receptor is G_s coupled, mediating cellular effects through increasing cellular levels of cAMP.

[edit] Characterized 5-HT receptors

Within these general classes of 5-HT receptors, a number of specific types have been characterized:

Summary of characterized 5-HT receptors, with selected agonist/antagonist agents
Receptor	Actions	Agonists	Antagonists
5-HT_1A	CNS: neuronal inhibition, behavioural effects (sleep, feeding, thermoregulation, anxiety; abnormalities in this receptor contribute to sudden infant death syndrome<ref name=SIDS>Paterson D.S. et al (2006). "Multiple Serotonergic Brainstem Abnormalities in Sudden Infant Death Syndrome". Journal of the American Medical Association 296: 2124–2132.</ref>)	buspirone	spiperone, methiothepin, ergotamine, yohimbine
5-HT_1B	CNS: presynaptic inhibition, behavioural effects; vascular: pulmonary vasoconstriction	ergotamine, sumatriptan	methiothepin, yohimbine, metergoline
5-HT_1D	CNS: locomotion; vascular: cerebral vasoconstriction	sumatriptan	methiothepin, yohimbine, metergoline, ergotamine
5-HT_2A	CNS: neuronal excitation, behavioural effects, learning; smooth muscle: contraction, vasoconstriction / dilatation; platelets: aggregation	α-methyl-5-HT, LSD (CNS), DOI	Nefazodone, trazodone, mirtazapine, ketanserin, cyproheptadine, pizotifen, LSD (PNS)
5-HT_2B	stomach: contraction	α-methyl-5-HT, LSD (CNS), DOI	yohimbine, LSD (PNS)
5-HT_2C	CNS, choroid plexus: cerebrospinal fluid (CSF) secretion	α-methyl-5-HT, agomelatine, LSD (CNS), DOI	mesulergine, agomelatine, LSD (PNS)
5-HT₃	CNS, PNS: neuronal excitation, anxiety, emesis	2-methyl-5-HT	metoclopramide(high doses), renzapride, ondansetron, alosetron, mirtazapine, memantine
5-HT₄	GIT, CNS: neuronal excitation, gastrointestinal motility	5-methoxytryptamine, metoclopramide, renzapride, tegaserod	GR113808
5-HT_5A	CNS (cortex, hippocampus, cerebellum): unknown	5-carboxytryptamine; LSD (partial agonist)<ref name="Nelson"/>	unknown
5-HT₆	CNS: unknown	LSD	SB271046 [2]
5-HT₇	CNS, GIT, blood vessels: unknown	5-carboxytryptamine, LSD	methiothepin

Note that there is no 5-HT_1C receptor since, after the receptor was cloned and further characterized, it was found to have more in common with the 5-HT₂ family of receptors and was redesignated as the 5-HT_2C receptor.

[edit] Therapeutic modulation

Various drugs are used to modulate the 5-HT system including some antidepressants, anxiolytics, and antiemetics.

[edit] 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).

[edit] 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.<ref>Svenningsson P, et al (2006). "Alterations in 5-HT1B receptor function by p11 in depression-like states". Science 311 (5757): 77–80. PMID 16400147.</ref>

[edit] 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.

[edit] 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.

[edit] References

Hiroi R et al, Biol Psychiatry 2006;60:288-295
Nash MW et al, 2005, Am J Med Genet B Neuropsychiatr Genet 135:33-37
Rang HP, Dale MM, Ritter JM, Moore PK (2003). Pharmacology (5 ed). Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4
Zhang X et al, 2005, Neuron 45:11-16