Serotonin

Efrain C Azmitia, New York University, New York, USA

Published online: October 2012

DOI: 10.1002/9780470015902.a0000124.pub2

Serotonin was discovered in 1949 and has been detected in all living aerobic organisms and in every tissue of the human body. In animals, serotonin functions both as a neurotransmitter and a trophic factor. As a neurotransmitter, serotonin can modify a variety of biological and behavioural functions, including sex, aggression, appetite, locomotor activity, learning and memory, sleep and hormonal secretion. As a trophic factor, serotonin is involved in the neuronal neurogenesis and neural maturation and has been implicated in the release of the cytoskeletal stability factor, S100b. The trophic actions of serotonin in human foetus begin soon after conception and are dependent on supplies provided by the mother's synthesis of serotonin in the gut by enterochromaffin cells and subsequent transfer in blood platelets. The baby not only gets most of its serotonin from the mother while in the uterus, but also makes serotonin very early in gestation when serotonin neurons appear in the midbrain, and serotonergic fibres soon spread throughout the brain. Serotonin at these early times is a differentiating factor and enhances cell mitosis, migration and maturation in subcortical, cortical and peripheral tissues. Serotonin neurons are sensitive to a large number of trophic, neurotransmitter, hormonal and sensory inputs and it has been proposed that this single chemical system serves as a brain homoeostatic regulatory. It is not surprising that serotonin is implicated in a variety of human illnesses, such as depression, Alzheimer's disease, attention deficit disorder, anorexia nervosa, bulimia, autism and schizophrenia. Therefore, when discussing the function of serotonin, it should be remembered that this molecule is ancient and predates the formation of the nervous system in both phylogeny and ontogeny.

Key Concepts:

  • Serotonin is made from oxygen, tryptophan and reducing cofactors by two enzymes: tryptophan hydroxylase and L-aromatic amino acid decarboxylase.
  • Tryptophan is able to absorb photons from sunlight (blue wave) and convert to biological energy and is essential for photosynthesis; producing oxygen in aerobic cells.
  • Serotonin made in large quantities in plants, where it appears to serve as regulatory mechanism to prevent excess oxygen from damaging cells.
  • Serotonin neurons in the human brain can activate at least 14 separate receptors and activation of the 5-HT2A receptor by psilocybin, mescaline and lysergic acid diethylamide produces hallucinations.
  • Serotonin in humans is made in a restricted midline area of brainstem called the raphe nuclei and has axonal connections to nearly every region of the brain.
  • Serotonin neurons are born early in gestation by the action of several genes including PET-1, a transcription factor specific for this neuronal system.
  • Serotonin acts as a trophic factor regulating cell proliferation, maturation and apoptosis by direct receptor actions as well as release of the glial protein, S100b.
  • A decrease in serotonin neurons is associated with depression and suicide, and neurons show evidence of neurodegeneration in autism, Alzheimer's disease, Parkinson's disease, frontal lobe dementia and Lewy-body dementia.
  • Serotonin is made within enterochromaffin cells in the gut and collected in blood platelets for transfer to all cells in the body and serves as a vehicle by which the mother can influence the development of her baby.
  • Melatonin is made from serotonin.

Keywords: evolution; plasticity; tryptophan hydroxylase; depression; autism; neurogenesis; platelets; raphe nucleus; S100b; melatonin

Figure 1. Structure of serotonin. Red, –OH; blue, nitrogen; white, carbon.
Figure 2. Role of serotonin in learning models in Aplysia. adenosine triphosphate, ATP; cyclic adenosine monophosphate, cAMP.
Figure 3. Biosynthetic pathway of serotonin (5-hydroxytryptamine, 5-HT) from l-tryptophan.
Figure 4. Amino acid sequence of the enzyme tryptophan hydroxylase, showing the regulatory (red, 1–186) and catalytic (blue, 187–444) segments.
Figure 5. The serotonin (5-hydroxytryptamine, 5-HT) terminal: storage, release, reuptake and metabolism. 5-hydroxyindole acetic acid, 5-HIAA; monoamine oxidase, MAO; tryptophan, Try; tryptophan hydroxylase, Try-OH.
Figure 6. Synthesis of melatonin from serotonin.
Figure 7. The main serotonin (5-hydroxytryptamine, 5-HT) projections to the brain and spinal cord of humans. Anterior colliculus, AC; anterior amygdala, AM; central sulcus, C. Sul; calcarine cortex, Cal; cingulum bundle, CB; corpus callosum, CC; cerebellum, Cer; corpus quadrigemini, CQ; nucleus central superior, pars dorsalis, CSD; nucleus central superior, pars medialis, CSM; dentate gyrus, DG; dorsal raphe cortical tract, DRCT; dorsal raphe nucleus, DRN; frontal cortex, F; frontal cortex, F. CTx; habenula, H; hippocampus, Hipp; layer I of cortex, I; inferior colliculus, IC; inferior olive, IO; interpeduncular nucleus, IP; fourth ventricle, IV; locus coerulerus, LC; lateral forebrain bundle, LFB; mammillary body, MB; medial forebrain bundle, MFB; nucleus raphe pallidus, NRPa; olfactory bulb, OB; raphe magnus, RM; nucleus raphe obscurus, RO; septum, S; stria medularis, SM; substantia nigra, SN; thalamus, T; temporal cortex, T. Ctx; ventroanterior forebrain pathway, VAFP.
Figure 8. Glial S100b or neuronal serotonin (5-HT) maintains the mature phenotype of the 5-HT target neurons and glial cells. When 5-HT brain levels are lowered, S100b levels decrease and the neuronal morphology shrinks due to cytoskeletal collapse. This can be done by decreasing 5-HT synthesis (PCPA) or naturally by reducing the amount of tryptophan in the diet (e.g. eating corn). When 5-HT levels are increased, S100b levels are increased and neuronal morphology is increased by microtubule stability. This can be done by injections of a SSRI or 5-HT1A receptor agonist or naturally by exposure to sunlight, a high tryptophan diet (e.g. eating nuts), or exercise. para-chlorophenylalanine, PCPA (5-HT synthesis inhibitor); 5-hydroxytryptamine type 1A, 5-HT1A; serotonin specific reuptake inhibitor, SSRI.
Figure 9. Structure of the 5-hydroxytryptamine type 1A (5-HT1A) receptor.
Figure 10. 5-Hydroxytryptamine (5-HT) type 1A and 5-HT2A receptors work in opposite directions. cyclic adenosine monophosphate, cAMP; protein kinase A, PKA; protein kinase C, PKC; guanine nucleotide-binding protein, G.
Figure 11. Neuronal instability. brain-derived neuronal factor, BDNF; guanosine triphosphatase-activating protein, GAP; 5-hydroxytryptamine, 5-HT (serotonin); mitogen-activated protein (kinase), MAP (K); protein kinase C, PKC; a microtubule-associated protein highly localised in axons, TAU; a tyrosine-receptor kinase that is stimulated by the growth factor BDNF, TrkB.
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 Further Reading
    book Iversen L, Iversen S, Bloom FE and Roth RH (2008) Introduction to Neuropsychopharmacology. USA: Oxford University Press.
    Jacobs BL and Azmitia EC (1992) Structure and function of the brain serotonin system. Physiological Reviews 72: 165–229.
    Whitaker-Azmitia PM, Druse M, Walker P and Lauder JM (1996) Serotonin as a developmental signal. Behavioural Brain Research 73(1-2): 19–29.

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Article Title: Serotonin
 
How to Cite close
Azmitia, Efrain C(Oct 2012) Serotonin. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000124.pub2]