Serotonin and Serotonin Transport in the Regulation of Lactation

  • Aaron M. Marshall
  • Laura L. Hernandez
  • Nelson D. Horseman


Serotonin (5-HT), classically known as a neurotransmitter involved in regulating sleep, appetite, memory, sexual behavior, neuroendocrine function and mood is also synthesized in epithelial cells located in many organs throughout the body, including the mammary gland. The function of epithelial 5-HT is dependent on the expression of the 5-HT receptors in a particular system. The conventional components of a classic 5-HT system are found within the mammary gland; synthetic enzymes (tryptophan hydroxylase I, aromatic amino acid decarboxylase), several 5-HT receptors and the 5-HT reuptake transporter (SERT). In the mammary gland, two actions of 5-HT through two different 5-HT receptor subtypes have been described: negative feedback on milk synthesis and secretion, and stimulation of parathyroid hormone related-protein, a calcium-mobilizing hormone. As with neuronal systems, the regulation of 5-HT activity is multifactorial, but one seminal component is reuptake of 5-HT from the extracellular space following its release. Importantly, the wide availability of selective 5-HT reuptake inhibitors (SSRI) allows the manipulation of 5-HT activity in a biological system. Here, we review the role of 5-HT in mammary gland function, review the biochemistry, genetics and physiology of SERT, and discuss how SERT is vital to the function of the mammary gland.


Epithelium Involution PTHrP SSRI Tight junctions 





serotonin transporter


selective serotonin reuptake inhibitor




tryptophan hydroxylase


aromatic amine decarboxylase


monoamine oxidase


5-hydroxyindole acetic acid


receptor activator of NF-κB ligand


parathyroid hormone related protein


vesicular monoamine transporters


  1. 1.
    Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H, et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science. 2003;299:76.PubMedCrossRefGoogle Scholar
  2. 2.
    Zhang X, Beaulieu JM, Sotnikova TD, Gainetdinov RR, Caron MG. Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science. 2004;305:217.PubMedCrossRefGoogle Scholar
  3. 3.
    Matsuda M, Imaoka T, Vomachka AJ, Gudelsky GA, Hou Z, Mistry M, et al. Serotonin regulates mammary gland development via an autocrine-paracrine loop. Dev Cell. 2004;6:193–203.PubMedCrossRefGoogle Scholar
  4. 4.
    Hernandez LL, Stiening CM, Wheelock JB, Baumgard LH, Parkhurst AM, Collier RJ. Evaluation of serotonin as a feedback inhibitor of lactation in the bovine. J Dairy Sci. 2008;91:1834–44.PubMedCrossRefGoogle Scholar
  5. 5.
    Boadle-Biber MC. Regulation of serotonin synthesis. Prog Biophys Mol Biol. 1993;60:1–15.PubMedCrossRefGoogle Scholar
  6. 6.
    Yamaguchi Y, Hayashi C. Simple determination of high urinary excretion of 5-hydroxyindole-3-acetic acid with ferric chloride. Clin Chem. 1978;24:149–50.PubMedGoogle Scholar
  7. 7.
    Rahman MK, Nagatsu T, Sakurai T, Hori S, Abe M, Matsuda M. Effect of pyridoxal phosphate deficiency on aromatic L-amino acid decarboxylase activity with L-DOPA and L-5-hydroxytryptophan as substrates in rats. Jpn J Pharmacol. 1982;32:803–11.PubMedCrossRefGoogle Scholar
  8. 8.
    Oldendorf WH. Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am J Physiol. 1971;221:1629–39.PubMedGoogle Scholar
  9. 9.
    Sanger GJ. 5-Hydroxytryptamine and the gastrointestinal tract: where next? Trends Pharmacol Sci. 2008;29:465–71.PubMedCrossRefGoogle Scholar
  10. 10.
    MacLean MR. Pulmonary hypertension, anorexigens and 5-HT: pharmacological synergism in action? Trends Pharmacol Sci. 1999;20:490–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Ramage AG, Villalon CM. 5-hydroxytryptamine and cardiovascular regulation. Trends Pharmacol Sci. 2008;29:472–81.PubMedCrossRefGoogle Scholar
  12. 12.
    Roth BL. The serotonin receptors: from molecular pharmacology to human therapeutics. Totowa: Humana Press; 2006.CrossRefGoogle Scholar
  13. 13.
    Hannon J, Hoyer D. Molecular biology of 5-HT receptors. Behav Brain Res. 2008;195:198–213.PubMedCrossRefGoogle Scholar
  14. 14.
    Stull MA, Pai V, Vomachka AJ, Marshall AM, Jacob GA, Horseman ND. Mammary gland homeostasis employs serotonergic regulation of epithelial tight junctions. Proc Natl Acad Sci U S A. 2007;104:16708–13.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Marshall AM, Nommsen-Rivers LA, Hernandez LL, Dewey KG, Chantry CJ, Gregerson KA, et al. Serotonin transport and metabolism in the mammary gland modulates secretory activation and involution. J Clin Endocrinol Metab. 2010;95:837–46.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Nguyen DA, Neville MC. Tight junction regulation in the mammary gland. J Mammary Gland Biol Neoplasia. 1998;3:233–46.PubMedCrossRefGoogle Scholar
  17. 17.
    Pai VP, Horseman ND. Biphasic regulation of mammary epithelial resistance by serotonin through activation of multiple pathways. J Biol Chem. 2008;283:30901–10.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Pai VP, Horseman ND. Multiple cellular responses to serotonin contribute to epithelial homeostasis. PLoS One. 2011;6:e17028.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Pai VP, Marshall AM. Intraluminal volume homeostasis: a common sertonergic mechanism among diverse epithelia. Commun Integr Biol. 2011;4:532–7.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Hernandez LL, Gregerson KA, Horseman ND. Mammary gland serotonin regulates parathyroid hormone-related protein and other bone-related signals. Am J Physiol Endocrinol Metab. 2012;302:E1009–15.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Laporta J, Moore SA, Peters MW, Peters TL, Hernandez LL. Short communication: circulating serotonin (5-HT) concentrations on day 1 of lactation as a potential predictor of transition-related disorders. J Dairy Sci. 2013;96:5146–50.PubMedCrossRefGoogle Scholar
  22. 22.
    Wysolmerski JJ. Parathyroid hormone-related protein: an update. J Clin Endocrinol Metab. 2012;97:2947–56.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Datta NS, Samra TA, Abou-Samra AB. Parathyroid hormone induces bone formation in phosphorylation-deficient PTHR1 knockin mice. Am J Physiol Endocrinol Metab. 2012;302:E1183–8.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Laporta J, Peters TL, Weaver SR, Merriman KE, Hernandez LL. Feeding 5-hydroxy-l-tryptophan during the transition from pregnancy to lactation increases calcium mobilization from bone in rats. Domest Anim Endocrinol. 2013;44:176–84.PubMedCrossRefGoogle Scholar
  25. 25.
    Horst RL, Goff JP, Reinhardt TA. Adapting to the transition between gestation and lactation: differences between rat, human and dairy cow. J Mammary Gland Biol Neoplasia. 2005;10:141–56.PubMedCrossRefGoogle Scholar
  26. 26.
    Daubner SC, Lauriano C, Haycock JW, Fitzpatrick PF. Site-directed mutagenesis of serine 40 of rat tyrosine hydroxylase. Effects of dopamine and cAMP-dependent phosphorylation on enzyme activity. J Biol Chem. 1992;267:12639–46.PubMedGoogle Scholar
  27. 27.
    Mockus SM, Kumer SC, Vrana KE. A chimeric tyrosine/tryptophan hydroxylase. The tyrosine hydroxylase regulatory domain serves to stabilize enzyme activity. J Mol Neurosci. 1997;9:35–48.PubMedCrossRefGoogle Scholar
  28. 28.
    Winge I, McKinney JA, Ying M, D’Santos CS, Kleppe R, Knappskog PM, et al. Activation and stabilization of human tryptophan hydroxylase 2 by phosphorylation and 14-3-3 binding. Biochem J. 2008;410:195–204.PubMedCrossRefGoogle Scholar
  29. 29.
    McKinney J, Knappskog PM, Pereira J, Ekern T, Toska K, Kuitert BB, et al. Expression and purification of human tryptophan hydroxylase from Escherichia coli and Pichia pastoris. Protein Expr Purif. 2004;33:185–94.PubMedCrossRefGoogle Scholar
  30. 30.
    McKinney J, Knappskog PM, Haavik J. Different properties of the central and peripheral forms of human tryptophan hydroxylase. J Neurochem. 2005;92:311–20.PubMedCrossRefGoogle Scholar
  31. 31.
    Johnston JP. Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol. 1968;17:1285–97.PubMedCrossRefGoogle Scholar
  32. 32.
    Knoll J, Magyar K. Some puzzling pharmacological effects of monoamine oxidase inhibitors. Adv Biochem Psychopharmacol. 1972;5:393–408.PubMedGoogle Scholar
  33. 33.
    Fornai F, Chen K, Giorgi FS, Gesi M, Alessandri MG, Shih JC. Striatal dopamine metabolism in monoamine oxidase B-deficient mice: a brain dialysis study. J Neurochem. 1999;73:2434–40.PubMedCrossRefGoogle Scholar
  34. 34.
    Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, et al. Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science. 1995;268:1763–6.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Grimsby J, Toth M, Chen K, Kumazawa T, Klaidman L, Adams JD, et al. Increased stress response and beta-phenylethylamine in MAOB-deficient mice. Nat Genet. 1997;17:206–10.PubMedCrossRefGoogle Scholar
  36. 36.
    Rudnick G, Nelson PJ. Reconstitution of 5-hydroxytryptamine transport from cholate-disrupted platelet plasma membrane vesicles. Biochemistry. 1978;17:5300–3.PubMedCrossRefGoogle Scholar
  37. 37.
    Gu H, Caplan MJ, Rudnick G. Cloned catecholamine transporters expressed in polarized epithelial cells: sorting, drug sensitivity, and ion-coupling stoichiometry. Adv Pharmacol. 1998;42:175–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Talvenheimo J, Fishkes H, Nelson PJ, Rudnick G. The serotonin transporter-imipramine “receptor”. J Biol Chem. 1983;258:6115–9.PubMedGoogle Scholar
  39. 39.
    Androutsellis-Theotokis A, Goldberg NR, Ueda K, Beppu T, Beckman ML, Das S, et al. Characterization of a functional bacterial homologue of sodium-dependent neurotransmitter transporters. J Biol Chem. 2003;278:12703–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Rudnick G. Serotonin transporters–structure and function. J Membr Biol. 2006;213:101–10.PubMedCrossRefGoogle Scholar
  41. 41.
    Larsen MB, Fjorback AW, Wiborg O. The C-terminus is critical for the functional expression of the human serotonin transporter. Biochemistry. 2006;45:1331–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Ahmed BA, Jeffus BC, Bukhari SI, Harney JT, Unal R, Lupashin VV, et al. Serotonin transamidates Rab4 and facilitates its binding to the C terminus of serotonin transporter. J Biol Chem. 2008;283:9388–98.PubMedCrossRefGoogle Scholar
  43. 43.
    Qian Y, Galli A, Ramamoorthy S, Risso S, DeFelice LJ, Blakely RD. Protein kinase C activation regulates human serotonin transporters in HEK-293 cells via altered cell surface expression. J Neurosci. 1997;17:45–57.PubMedGoogle Scholar
  44. 44.
    Zhu CB, Hewlett WA, Feoktistov I, Biaggioni I, Blakely RD. Adenosine receptor, protein kinase G, and p38 mitogen-activated protein kinase-dependent up-regulation of serotonin transporters involves both transporter trafficking and activation. Mol Pharmacol. 2004;65:1462–74.PubMedCrossRefGoogle Scholar
  45. 45.
    Beckman ML, Bernstein EM, Quick MW. Protein kinase C regulates the interaction between a GABA transporter and syntaxin 1A. J Neurosci. 1998;18:6103–12.PubMedGoogle Scholar
  46. 46.
    Wong A, Zhang YW, Jeschke GR, Turk BE, Rudnick G. Cyclic GMP-dependent stimulation of serotonin transport does not involve direct transporter phosphorylation by cGMP-dependent protein kinase. J Biol Chem. 2012;287:36051–8.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Erickson JD, Eiden LE, Hoffman BJ. Expression cloning of a reserpine-sensitive vesicular monoamine transporter. Proc Natl Acad Sci U S A. 1992;89:10993–7.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Erickson JD, Eiden LE. Functional identification and molecular cloning of a human brain vesicle monoamine transporter. J Neurochem. 1993;61:2314–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Erickson JD, Schafer MK, Bonner TI, Eiden LE, Weihe E. Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter. Proc Natl Acad Sci U S A. 1996;93:5166–71.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Merickel A, Edwards RH. Transport of histamine by vesicular monoamine transporter-2. Neuropharmacology. 1995;34:1543–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132:397–414.PubMedCrossRefGoogle Scholar
  52. 52.
    Fabre V, Boutrel B, Hanoun N, Lanfumey L, Fattaccini CM, Demeneix B, et al. Homeostatic regulation of serotonergic function by the serotonin transporter as revealed by nonviral gene transfer. J Neurosci. 2000;20:5065–75.PubMedGoogle Scholar
  53. 53.
    Marshall AM, Pai VP, Sartor MA, Horseman ND. In vitro multipotent differentiation and barrier function of a human mammary epithelium. Cell Tissue Res. 2009;335:383–95.PubMedCrossRefGoogle Scholar
  54. 54.
    Nguyen DA, Parlow AF, Neville MC. Hormonal regulation of tight junction closure in the mouse mammary epithelium during the transition from pregnancy to lactation. J Endocrinol. 2001;170:347–56.PubMedCrossRefGoogle Scholar
  55. 55.
    Gorman JR, Kao K, Chambers CD. Breastfeeding among women exposed to antidepressants during pregnancy. J Hum Lact. 2012;28:181–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Sghendo L, Mifsud J. Understanding the molecular pharmacology of the serotonergic system: using fluoxetine as a model. J Pharm Pharmacol. 2012;64:317–25.PubMedCrossRefGoogle Scholar
  57. 57.
    Brambilla P, Cipriani A, Hotopf M, Barbui C. Side-effect profile of fluoxetine in comparison with other SSRIs, tricyclic and newer antidepressants: a meta-analysis of clinical trial data. Pharmacopsychiatry. 2005;38:69–77.PubMedCrossRefGoogle Scholar
  58. 58.
    Fabre V, Beaufour C, Evrard A, Rioux A, Hanoun N, Lesch KP, et al. Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter. Eur J Neurosci. 2000;12:2299–310.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Aaron M. Marshall
    • 1
  • Laura L. Hernandez
    • 2
  • Nelson D. Horseman
    • 3
  1. 1.Department of Medical EducationUniversity of CincinnatiCincinnatiUSA
  2. 2.Department of Dairy ScienceUniversity of WisconsinMadisonUSA
  3. 3.Department of Molecular and Cellular Physiology, Program in Systems Biology and PhysiologyUniversity of CincinnatiCincinnatiUSA

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