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Translational Neuroscience

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Expression of 5HT-related genes after perinatal treatment with 5HT agonists

Sofia Blažević
  • Department of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, HR-10 000, Zagreb, Croatia
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/ Dubravka Hranilović
  • Department of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, HR-10 000, Zagreb, Croatia
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Published Online: 2013-06-09 | DOI: https://doi.org/10.2478/s13380-013-0124-3


Serotonin (5HT) is a biologically active amine with diverse roles in the mammalian organism. Developmental alterations in 5HT homeostasis could lead to exposure of the developing brain to non-optimal serotonin concentrations that may result in developmental and behavioral deficits. In order to explore the molecular basis of the effects of developmental disturbances on 5HT metabolism on adult central 5HT homeostasis, observed in our previous studies, we measured changes in gene expression of the neuronal 5HT-regulating proteins in adult animals after perinatal treatment with the immediate 5HT precursor 5-hydroxytryptophan (5HTP, 25 mg/kg), or monoamine oxidase (MAO) inhibitor tranylcypromine (TCP 2 mg/kg), during the period of the most intensive development of 5HT neurons — from gestational day 12 until postnatal day 21. Adult animals were sacrificed and the relative mRNA levels for tryptophan hydroxylase 2, MAO A, MAO B, receptors 5HT1A and 5HT2A, 5HT transporter (5HTT) and vesicular monoamine transporter (VMAT) were determined in the raphe nuclei region and prefrontal cortex using Real-Time Relative qRT-PCR. In comparison to the saline treated animals, treatment with 5HTP caused mild but significant increase in MAO A and MAO B mRNA abundance. TCP-treated animals, besides an increase in mRNA abundance for both MAO genes, displayed significantly increased 5HTT and VMAT2 mRNA levels and significantly decreased 5HT1A receptor mRNA levels. Our results suggest that perinatal exposure of rats to 5HTP, and especially TCP, induces long-lasting/permanent changes in the expression of 5HT-regulating genes, that presumably underlie 5HT-related neurochemical and behavioral changes in adult animals.

Keywords: Serotonin; Tranylcypromine; 5-hydroxytryptophan; mRNA; Rat brain; Perinatal treatment

  • [1] Berger M., Gray J.A., Roth B.L., The expanded biology of serotonin, Annu. Rev. Med., 2009, 60, 355–366 http://dx.doi.org/10.1146/annurev.med.60.042307.110802CrossrefWeb of ScienceGoogle Scholar

  • [2] Whitaker-Azmitia P.M., Serotonin and brain development: role in human developmental diseases, Brain Res. Bull., 2001, 56, 479–485 http://dx.doi.org/10.1016/S0361-9230(01)00615-3CrossrefGoogle Scholar

  • [3] Catalano M., Functionally gene-linked polymorphic regions and genetically controlled neurotransmitters metabolism, Eur. Neuropsychopharmacol., 2001, 11, 431–439 http://dx.doi.org/10.1016/S0924-977X(01)00120-1CrossrefGoogle Scholar

  • [4] Lesch K.P., Variation of serotonergic gene expression: neurodevelopment and the complexity of response to psychopharmacologic drugs, Eur. Neuropsychopharm., 2001, 11, 457–474 http://dx.doi.org/10.1016/S0924-977X(01)00123-7CrossrefGoogle Scholar

  • [5] Racke K., Reimann A., Schwörer H., Kilbinger H., Regulation of 5-HT release from enterochromaffin cells, Behav. Brain Res., 1995, 73, 83–87 http://dx.doi.org/10.1016/0166-4328(96)00075-7CrossrefGoogle Scholar

  • [6] Walther D.J., Bader M., A unique central tryptophan hydroxylase isoform, Biochem. Pharmacol., 2003, 66, 1673–1680 http://dx.doi.org/10.1016/S0006-2952(03)00556-2CrossrefGoogle Scholar

  • [7] Henry J.P., Sagné C., Bedet C., Gasnier B., The vesicular monoamine transporter: from chromaffin granule to brain, Neurochem. Int., 1998, 32, 227–246 http://dx.doi.org/10.1016/S0197-0186(97)00092-2CrossrefGoogle Scholar

  • [8] Torres G.E., Gainetdinov R.R., Caron M.G., Plasma membrane monoamine transporters: structure, regulation and function, Nat. Rev. Neurosci., 2003, 4, 13–25 http://dx.doi.org/10.1038/nrn1008CrossrefGoogle Scholar

  • [9] Hoyer D., Hannon J.P., Martin G.R., Molecular, pharmacological and functional diversity of 5-HT receptors, Pharmacol. Biochem. Behav., 2002, 71, 533–554 http://dx.doi.org/10.1016/S0091-3057(01)00746-8CrossrefGoogle Scholar

  • [10] Schwörer H., Ramadori G., Autoreceptors can modulate 5-hydroxytryptamine release from porcine and human small intestine in vitro, Naunyn Schmiedebergs Arch. Pharmacol., 1998, 357, 548–552 http://dx.doi.org/10.1007/PL00005206CrossrefGoogle Scholar

  • [11] Billett E., Monoamine oxidase (MAO) in human peripheral tissues, Neurotoxicology, 2004, 25, 139–148 http://dx.doi.org/10.1016/S0161-813X(03)00094-9CrossrefGoogle Scholar

  • [12] Davies K., Richardson G., Akmentin W., Acuff V., Fenstermacher J., The microarchitecture of cerebral vessels, In: Courad P., Scherman D. (Eds.), Biology and physiology of the blood-brain barrier: transport, cellular interactions, and brain pathologies, Plenum Press, New York, 1996, 83–91 http://dx.doi.org/10.1007/978-1-4757-9489-2_15CrossrefGoogle Scholar

  • [13] Cote F., Fligny C., Bayard E., Launay J.-M., Gershon M.D., Mallet J., et al., Maternal serotonin is crucial for murine embryonic development, Proc. Natl. Acad. Sci. USA, 2007, 104, 329–334 http://dx.doi.org/10.1073/pnas.0606722104CrossrefGoogle Scholar

  • [14] Bonnin A., Goeden N., Chen K., Wilson M.L., King J., Shih J.C., et al., A transient placental source of serotonin for the fetal forebrain, Nature, 2011, 472, 347–350 http://dx.doi.org/10.1038/nature09972CrossrefWeb of ScienceGoogle Scholar

  • [15] Hadjikhani N., Serotonin, pregnancy and increased autism prevalence: is there a link?, Med. Hypotheses, 2010, 74, 880–883 http://dx.doi.org/10.1016/j.mehy.2009.11.015CrossrefWeb of ScienceGoogle Scholar

  • [16] Nijenhuis C.M., Ter Horst P.G.J., De Jong-van den Berg L.T.W., Wilffert B., Disturbed development of the enteric nervous system after in utero exposure of selective serotonin re-uptake inhibitors and tricyclic antidepressants. Part 1: Literature review, Br. J. Clin. Pharmacol., 2012, 73, 16–26 http://dx.doi.org/10.1111/j.1365-2125.2011.04075.xWeb of ScienceGoogle Scholar

  • [17] Lauder J.M., Ontogeny of the serotonergic system in the rat: serotonin as a developmental signal, Ann. NY Acad. Sci., 1990, 600, 297–313 http://dx.doi.org/10.1111/j.1749-6632.1990.tb16891.xCrossrefGoogle Scholar

  • [18] Blažević S., Dolenec P., Hranilović D., Physiological consequences of perinatal treatment of rats with 5-hydroxytryptophan, Period. Biol., 2011, 113, 81–86 Google Scholar

  • [19] Hranilović D., Blažević S., Ivica N., Čičin-Šain L., Oreškovic D., The effects of the perinatal treatment with 5-hydroxytryptophan or tranylcypromine on the peripheral and central serotonin homeostasis in adult rats, Neurochem. Int., 2011, 59, 202–207 http://dx.doi.org/10.1016/j.neuint.2011.05.003CrossrefWeb of ScienceGoogle Scholar

  • [20] Blažević S., Jurčić Z., Hranilović D., Perinatal treatment of rats with MAO inhibitor tranylcypromine, Transl. Neurosci., 2010, 1, 49–54 http://dx.doi.org/10.2478/v10134-010-0006-yCrossrefWeb of ScienceGoogle Scholar

  • [21] Blazević S., Čolić L., Čulig L., Hranilović D., Anxiety-like behavior and cognitive flexibility in adult rats perinatally exposed to increased serotonin concentrations, Behav. Brain Res., 2012, 230, 175–181 http://dx.doi.org/10.1016/j.bbr.2012.02.001CrossrefWeb of ScienceGoogle Scholar

  • [22] Paxinos G., Watson C., The rat brain in stereotaxic coordinates, 6th ed., Academic Press, London, 2007, 456 Google Scholar

  • [23] Birdsall T.C., 5-Hydroxytryptophan: a clinically-effective serotonin precursor, Altern. Med. Rev., 1998, 3, 271–280 Google Scholar

  • [24] Celada P., Artigas F., Monoamine oxidase inhibitors increase preferentially extracellular 5-hydroxytryptamine in the midbrain raphe nuclei. A brain microdialysis study in the awake rat, Naunyn Schmiedebergs Arch. Pharmacol., 1993, 347, 583–590 http://dx.doi.org/10.1007/BF00166940Google Scholar

  • [25] Green A.R., Youdim M.B., Effects of monoamine oxidase inhibition by clorgyline, deprenil or tranylcypromine on 5-hydroxytryptamine concentrations in rat brain and hyperactivity following subsequent tryptophan administration, Br. J. Pharmacol., 1975, 55, 415–422 http://dx.doi.org/10.1111/j.1476-5381.1975.tb06946.xGoogle Scholar

  • [26] Johnston J.P., Some observations upon a new inhibitor of monoamine oxidase in brain tissue, Biochem. Pharmacol., 1968, 17, 1285–1297 http://dx.doi.org/10.1016/0006-2952(68)90066-XCrossrefGoogle Scholar

  • [27] Sleight A.J., Marsden C.A., Martin K.F., Palfreyman M.G., Relationship between extracellular 5-hydroxytryptamine and behaviour following monoamine oxidase inhibition and L-tryptophan, Drugs, 1988, 93, 303–310 Google Scholar

  • [28] Lesch K.P., Wolozin B.L., Murphy D.L., Riederer P., Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter, J. Neurochem., 1993, 60, 2319–2322 http://dx.doi.org/10.1111/j.1471-4159.1993.tb03522.xCrossrefGoogle Scholar

  • [29] Carkaci-Salli N., Salli U., Kuntz-Melcavage K.L., Pennock M.M., Ozgen H., Tekin I., et al., TPH2 in the ventral tegmental area of the male rat brain, Brain Res. Bull., 2011, 84, 376–380 http://dx.doi.org/10.1016/j.brainresbull.2011.01.006CrossrefGoogle Scholar

  • [30] Chalmers D.T., Watson S.J., Comparative anatomical distribution of 5-HT1A receptor mRNA and 5-HT1A binding in rat brain—a combined in situ hybridisation/in vitro receptor autoradiographic study, Brain Res., 1991, 561, 51–60 http://dx.doi.org/10.1016/0006-8993(91)90748-KCrossrefGoogle Scholar

  • [31] Mengod G., Pompeiano M., MartÍnez-Mir M.I., Palacios J.M., Localization of the mRNA for the 5-HT2 receptor by in situ hybridization histochemistry. Correlation with the distribution of receptor sites, Brain Res., 1990, 524, 139–143 http://dx.doi.org/10.1016/0006-8993(90)90502-3CrossrefGoogle Scholar

  • [32] Jahng J., Houpt T., Wessel T., Localization of monoamine oxidase A and B mRNA in the rat brain by in situ hybridization, Synapse, 1997, 36, 30–36 http://dx.doi.org/10.1002/(SICI)1098-2396(199701)25:1<30::AID-SYN4>3.0.CO;2-GCrossrefGoogle Scholar

  • [33] Hansson S.R., Mezey E., Hoffman B.J., Ontogeny of vesicular monoamine transporter mRNAs VMAT1 and VMAT2. II. Expression in neural crest derivatives and their target sites in the rat, Dev. Brain Res., 1998, 110, 159–174 http://dx.doi.org/10.1016/S0165-3806(98)00103-5CrossrefGoogle Scholar

  • [34] Owesson C.A., Hopwood S.E., Callado L.F., Seif I., McLaughlin D.P., Stamford J. A., Altered presynaptic function in monoaminergic neurons of monoamine oxidase-A knockout mice, Eur. J. Neurosci., 2002, 15, 1516–1522 http://dx.doi.org/10.1046/j.1460-9568.2002.01986.xCrossrefGoogle Scholar

  • [35] Holschneider D.P., Chen K., Seif I., Shih J.C., Biochemical, behavioral, physiologic, and neurodevelopmental changes in mice deficient in monoamine oxidase A or B, Brain Res., 2001, 56, 453–462 Google Scholar

  • [36] Thompson B., Stanwood G., Pleiotropic effects of neurotransmission during development: modulators of modularity, J. Autism Dev. Disord., 2009, 39, 260–268 http://dx.doi.org/10.1007/s10803-008-0624-0CrossrefWeb of ScienceGoogle Scholar

  • [37] Lesch K.P., Moessner R., Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders?, Biol. Psychiat., 1998, 44, 179–192 http://dx.doi.org/10.1016/S0006-3223(98)00121-8CrossrefGoogle Scholar

  • [38] Baum A.L., Misri S., Selective serotonin-reuptake inhibitors in pregnancy and lactation, Harvard Rev. Psychiat., 1996, 4, 117–125 http://dx.doi.org/10.3109/10673229609030534CrossrefGoogle Scholar

  • [39] Borue X., Chen J., Condron B.G., Developmental effects of SSRIs: lessons learned from animal studies, Int. J. Dev. Neurosci., 2007, 25, 341–347 http://dx.doi.org/10.1016/j.ijdevneu.2007.06.003CrossrefGoogle Scholar

  • [40] Frederick A., Stanwood G., Drugs, biogenic amine targets and the developing brain, Dev. Neurosci., 2009, 31, 7–22 http://dx.doi.org/10.1159/000207490CrossrefWeb of ScienceGoogle Scholar

  • [41] Henderson M., McMillen B., Changes in dopamine, serotonin and their metabolites in discrete brain areas of rat offspring after in utero exposure to cocaine or related drugs, Teratology, 2005, 48, 421–430 http://dx.doi.org/10.1002/tera.1420480506CrossrefGoogle Scholar

  • [42] Kelly P.A.T., Ritchie I.M., Quate L., McBean D.E., Olverman H.J., Functional consequences of perinatal exposure to 3,4-methylenedioxymethamphetamine in rat brain, Br. J. Pharmacol., 2002, 137, 963–970 http://dx.doi.org/10.1038/sj.bjp.0704961CrossrefGoogle Scholar

  • [43] Pawluski J., Perinatal selective serotonin reuptake inhibitor exposure: impact on brain development and neural plasticity, Neuroendocrinology, 2012, 95, 39–46 http://dx.doi.org/10.1159/000329293Web of ScienceCrossrefGoogle Scholar

  • [44] Lauder J.M., Liu J., Grayson D.R., In utero exposure to serotonergic drugs alters neonatal expression of 5-HT(1A) receptor transcripts: a quantitative RT-PCR study, Int. J. Dev. Neurosci., 2000, 18, 171–176 http://dx.doi.org/10.1016/S0736-5748(99)00085-4CrossrefGoogle Scholar

  • [45] Hranilović D., Novak R., Babić M., Novokmet M., Bujas-Petković Z., Jernej B., et al., Hyperserotonemia in autism: the potential role of 5HT-related gene variants, Coll. Antropol., 2008, 32, 75–80 Google Scholar

  • [46] Hranilović D., Bujas-Petković Z., Tomičić M., Bordukalo-Nikšić T., Blažević S., Čičin-Šain L., Hyperserotonemia in autism: activity of 5HT-associated platelet proteins, J. Neural. Transm., 2009, 116, 493–501 http://dx.doi.org/10.1007/s00702-009-0192-2Web of ScienceCrossrefGoogle Scholar

About the article

Published Online: 2013-06-09

Published in Print: 2013-06-01

Citation Information: Translational Neuroscience, Volume 4, Issue 2, Pages 165–171, ISSN (Online) 2081-6936, ISSN (Print) 2081-3856, DOI: https://doi.org/10.2478/s13380-013-0124-3.

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