Serotonin

Abstract

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.

close

References

Aghajanian GK and Marek GJ (1999) Serotonin and hallucinogens. Neuropsychopharmacology 21(Suppl. 2): 16S–23S.

Akbari HM, Whitaker‐Azmitia PM and Azmitia EC (1994) Prenatal cocaine decreases the trophic factor S‐100 beta and induced microcephaly: reversal by postnatal 5‐HT1A receptor agonist. Neuroscience Letters 170(1): 141–144.

Araneda S, Gamrani H, Font C et al. (1980) Retrograde axonal transport following injection of [3H]‐serotonin into the olfactory bulb. II. Radioautographic study. Brain Research 196: 417–427.

Azmitia EC (1999) Serotonin neurons, neuroplasticity, and homeostasis of neural tissue. Neuropsychopharmacology 21(Suppl. 2): 33S–45S.

Azmitia EC (2001) Modern views on an ancient chemical: serotonin effects on cell proliferation, maturation, and apoptosis. Brain Research Bulletin 56(5): 413–424.

Azmitia EC (2007) Cajal and brain plasticity: insights relevant to emerging concepts of mind. Brain Research Review 55(2): 395–405.

Azmitia EC (2010) The evolution of the serotonin system. In: Muller C and Jacobs B (eds) Handbook of the Behavioral Neurobiology of Serotonin, Chap. 1, pp. 3–22. Elsevier.

Azmitia EC, Buchan AM and Williams JH (1978) Structural and functional restoration by collateral sprouting of hippocampal 5‐HT axons. Nature 274: 374–376.

Azmitia EC and Gannon P (1983) The ultrastructural localization of serotonin immunoreactivity in myelinated and unmyelinated axons within the medial forebrain bundle of rat and monkey. Journal of Neuroscience 3(10): 2083–2090.

Azmitia EC and Nixon R (2008) Dystrophic serotonergic axons in neurodegenerative diseases. Brain Research 1217: 185–194.

Azmitia EC and Segal M (1978) An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat. Journal of Comparative Neurology 179: 641–667.

Azmitia EC, Singh JS, Hou XP and Wegiel J (2012) Dystrophic serotonin axons in postmortem brains from young autism patients. Anatomical Record 294(10): 1653–1662.

Beaudet A and Descarries L (1978) The monoamine innervation of rat cerebral cortex: synaptic and nonsynaptic axon terminals. Neuroscience 3(10): 851–860.

Bloom FE and Costa E (1971) The effects of drugs on serotonergic nerve terminals. Advances in Cytopharmacology 1: 379–395.

Brodie BB and Shore PA (1957) A concept for a role of serotonin and norepinephrine as chemical mediators in the brain. Annals of the New York Academy of Sciences 66: 631–642.

Dahlstrom A and Fuxe K (1964) Evidence for the existence of monoamine‐containing neurons in the central nervous system. I. Demonstration of monoamines in cell bodies of brain neurons. Acta Physiologica Scandinavica 62(Suppl. 232): 1–55.

Fuller RW and Wong DT (1977) Inhibition of serotonin reuptake. Federation Proceedings 36(8): 2154–2158.

Gershon MD (2009) Enteric serotonergic neurones … finally!. Journal of Physiology 587(Pt 3): 507.

Grahame‐Smith DG (1967) The biosynthesis of 5‐hydroxytryptamine in brain. Biochemical Journal 105(1): 351–360.

Grenett HE, Ledley FD, Reed LL and Woo SL (1987) Full‐length cDNA for rabbit tryptophan hydroxylase: functional domains and evolution of aromatic amino acid hydroxylases. Proceedings of the National Academy of Sciences of the USA 84(16): 5530–5534.

Griffiths R, Richards W, Johnson M, McCann U and Jesse R (2008) Mystical‐type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. Journal of Psychopharmacology 22(6): 621–632.

Hartig PR (1989) Molecular biology of 5‐HT receptors. Trends in Pharmacological Science 10: 64–69.

Harvey JA, Schlosberg AJ and Yunger LM (1975) Behavioral correlates of serotonin depletion. Federation Proceedings 34: 1796–1801.

Hendricks T, Francis N, Fyodorov D and Deneris ES (1999) The ETS domain factor Pet‐1 isa n early and precise marker of central serotonin neurons and interacts with a conserved element in serotonergic genes. Journal of Neuroscience 9(23): 10348–10356.

Hofmann A (1983) LSD My Problem Child: Reflections on Sacred Drugs, Mysticism and Science. New York, NY: J.P. Tarcher, Inc.

Hoyer D, Clarke DE, Fozard JR et al. (1994) International Union of Pharmacology classification of receptors for 5‐hydroxytramine (serotonin). Pharmacological Reviews 46: 157–203.

Jacobs BL, Martín‐Cora FJ and Fornal CA (2002) Activity of medullary serotonergic neurons in freely moving animals. Brain Research. Brain Research Reviews 40(1–3): 45–52.

Koe BK and Weissman A (1966) p‐Chlorophenylalanine: a specific depletor of brain serotonin. Journal of Pharmacology and Experimental Therapeutics 154: 499–516.

Kosofsky BE and Molliver ME (1987) The seroninergic innervation of cerebral cortex: different classes of axon terminals arise from dorsal and median raphe nuclei. Synapse 1: 153–168.

Levitt P, Pintar JE and Breakefield XO (1982) Immunocytochemical demonstration of monoamine oxidase B in brain astrocytes and serotonergic neurons. Proceedings of the National Academy of Sciences of the USA 79(20): 6385–6389.

Molliver ME (1987) Serotonergic neuronal systems: what their anatomic organization tells us about function. Journal of Clinical Psychopharmacology 7(Suppl. 6): 3S–23S.

Peroutka SJ and Howell TA (1994) The molecular evolution of G protein‐coupled receptors: focus on 5‐hydroxytryptamine receptors. Neuropharmacology 33: 319–324.

van Praag HM (1974) Toward a biochemical classification of depression. Advances in Biochemical Psychopharmacology 11(0): 357–368.

Russo S, Kema IP, Bosker F, Haavik J and Korf J (2009) Tryptophan as an evolutionarily conserved signal to brain serotonin: molecular evidence and psychiatric implications. World Journal of Biological Psychiatry 10(4): 258–268.

Shulgin A and Shulgin A (1991) Pihkal: a Chemical Love Story. Berkeley, CA: Transform Press.

Wallace JA and Lauder JM (1983) Development of the serotonergic system in the rat embryo: an immunocytochemical study. Brain Research Bulletin 10(4): 459–479.

Whitaker‐Azmitia PM (1999) The discovery of serotonin and its role in neuroscience. Neuropsychopharmacology 21(Suppl. 2): 2S–8S.

Whitaker‐Azmitia PM and Azmitia EC (1994) Astroglial 5‐HT1a receptors and S‐100 beta in development and plasticity. Perspectives on Developmental Neurobiology 2(3): 233–238.

Further Reading

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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]