Developing brain as a source of circulating norepinephrine in rats during the critical period of morphogenesis

  • Aliia R. Murtazina
  • Yulia O. Nikishina
  • Nadezhda S. Bondarenko
  • Liliya K. Dil’mukhametova
  • Anna Ya. Sapronova
  • Michael V. UgrumovEmail author
Original Article


The development of individual organs and the whole organism is under the control by morphogenetic factors over the critical period of morphogenesis. This study was aimed to test our hypothesis that the developing brain operates as an endocrine organ during morphogenesis, in rats during the perinatal period (Ugrumov in Neuro Chem 35:837–850, 2010). Norepinephrine, which is a morphogenetic factor, was used as a marker of the endocrine activity of the developing brain, although it is also secreted by peripheral organs. In this study, it was first shown that the concentration of norepinephrine in the peripheral blood of neonatal rats is sufficient to ensure the morphogenetic effect on the peripheral organs and the brain itself. Using pharmacological suppression of norepinephrine production in the brain, but not in peripheral organs, it was shown that norepinephrine is delivered from the brain to the general circulation in neonatal rats, that is, during morphogenesis. In fact, even partial suppression of norepinephrine production in the brain of neonatal rats led to a significant decrease of norepinephrine concentration in plasma, suggesting that at this time the brain is an important source of circulating norepinephrine. Conversely, the suppression of the production of norepinephrine in the brain of prepubertal rats did not cause a change in its concentration in plasma, showing no secretion of brain-derived norepinephrine to the bloodstream after morphogenesis. The above data support our hypothesis that morphogenetic factors, including norepinephrine, are delivered from the developing brain to the bloodstream, which occurs only during the critical period of morphogenesis.


General Circulation Developing brain Norepinephrine Morphogenesis Rat 





Dopamine ß-hydroxylase


Embryonic day


High performance liquid chromatography with electrochemical detection








Phosphate buffer saline


Postnatal day


Authors contributions

MVU created the concept and design of the study, interpreted the experimental data; ARM, YON, NSB, AYS performed experiments, analyzed and interpreted biochemical data; LKD carried out immunohistochemistry and image analysis, prepared figures. All authors have approved the final manuscript and agree to be accountable for all aspects of the work.


This research was supported by the Russian Science Foundation: Grants № 14-15-01122 and № 17-14-01422 for the study of the brain-blood barrier permeability in newborn and adult rats, respectively.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. Asano Y (1971) The maturation of the circadian rhythm of brain norepinephrine and serotonin in the rat. Life Sci 10(15):883–894CrossRefGoogle Scholar
  2. Ashwell KW, Paxinos G (2008) Atlas of the developing rat nervous system, 3rd edn. Elsevier Academic Press, San DiegoGoogle Scholar
  3. Bauer HC, Krizbai IA, Bauer H, Traweger A (2014) “You Shall Not Pass”—tight junctions of the blood brain barrier. Front Neurosci 8:392. CrossRefGoogle Scholar
  4. Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, Gu C (2014) MSFD2A is critical for the formation and function of the blood brain barrier. Nature 509:507. CrossRefGoogle Scholar
  5. Berger-Sweeney J, Hohmann CF (1997) Behavioral consequences of abnormal cortical development: insights into developmental disabilities. Behav Brain Res 86:121–142. CrossRefGoogle Scholar
  6. Blanchi BC, Sieweke MH (2008) Transcription factor control of central respiratory neuron development. In: Gaultier C (ed) Genetic basis for respiratory control disorders. Springer, New York, pp 191–221CrossRefGoogle Scholar
  7. Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, Verna JM (2001) Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 65:135–172. CrossRefGoogle Scholar
  8. Breese GR, Traylor TD (1972) Developmental characteristics of brain catecholamines and tyrosine hydroxylase in the rat: effects of 6‐hydroxydopamine. Br J Pharmacol 44(2):210–222. CrossRefGoogle Scholar
  9. Daneman R (2012) The blood–brain barrier in health and disease. Ann Neurol 72:648–672. CrossRefGoogle Scholar
  10. Davids E, Zhang K, Kula NS, Tarazi FI, Baldessarini RJ (2002) Effects of norepinephrine and serotonin transporter inhibitors on hyperactivity induced by neonatal 6-hydroxydopamine lesioning in rats. J Pharmacol Exp Ther 301:1097–1102. CrossRefGoogle Scholar
  11. Espinasse I, Iourgenko V, Defer N, Samson F, Hanoune J, Mercadier JJ (1995) Type V, but not type VI, adenylyl cyclase mRNA accumulates in the rat heart during ontogenic development. Correlation with increased global adenylyl cyclase activity. J Mol Cell Cardiol 27:1789–1795. CrossRefGoogle Scholar
  12. Felten DL, Hallman H, Jonsson G (1982) Evidence for a neurotrophic role of noradrenaline neurons in the postnatal development of rat cerebral cortex. J Neurocytol 11:119–135CrossRefGoogle Scholar
  13. Fernandez-Lopez D, Faustino J, Daneman R, Zhou L, Lee SY, Derugin N, Wendland MF, Vexler ZS (2012) Blood–brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat. J Neurosci 32:9588–9600. CrossRefGoogle Scholar
  14. Goldstein DS, Eisenhofer G, Kopin IJ (2003) Sources and significance of plasma levels of catechols and their metabolites in humans. J Pharmacol Exp Ther 305:800–811. CrossRefGoogle Scholar
  15. Gorski RA (1985) The 13th JAF Stevenson Memorial Lecture Sexual differentiation of the brain: possible mechanisms and implications. Can J Physiol Pharmacol 63:577–594. CrossRefGoogle Scholar
  16. Guerra A, King J, Alajajian B, Isgor E, Digicaylioglu M (2011) Occludin and claudin-5 are comparably abundant and co-localized in the rat’s blood brain barrier from late gestation to adulthood. EJ Neonatol Res 1:31–43Google Scholar
  17. Happe HK, Coulter CL, Gerety ME, Sanders JD, O’Rourke M, Bylund DB, Murrin LC (2004) Alpha-2 adrenergic receptor development in rat CNS: an autoradiographic study. Neurosci 123:167–178. CrossRefGoogle Scholar
  18. Hildreth V, Anderson RH, Henderson DJ (2009) Autonomic innervation of the developing heart: origins and function. Clin Anat 22:36–46. CrossRefGoogle Scholar
  19. Huber K, Kalcheim C, Unsicker K (2009) The development of the chromaffin cell lineage from the neural crest. Auton Neurosci 151:10–16. CrossRefGoogle Scholar
  20. Keshles O, Levitzki A (1984) The ontogenesis of β-adrenergic receptors and of adenylate cyclase in the developing rat brain. Biochem Pharmacol 33:3231–3233. CrossRefGoogle Scholar
  21. Khazipov R, Zaynutdinova D, Ogievetsky E, Valeeva G, Mitrukhina O, Manent JB, Represa A (2015) Atlas of the postnatal rat brain in stereotaxic coordinates. Front Neuroanat 9:161. CrossRefGoogle Scholar
  22. Kitamura Y, Mochii M, Kodama R, Agata K, Watanabe K, Eguchi G, Nomura Y (1989) Ontogenesis of α2-Adrenoceptor coupling with GTP-binding proteins in the rat telencephalon. J Neurochem 53:249–257. CrossRefGoogle Scholar
  23. Kolacheva AA, Kozina EA, Volina EV, Ugryumov MV (2014) Time course of degeneration of dopaminergic neurons and respective compensatory processes in the nigrostriatal system in mice. Dokl Biol Sci 456:160–164. CrossRefGoogle Scholar
  24. Kostrzewa RM (2007) The blood-brain barrier for catecholamines—revisited. Neurotox Res 11:261–271CrossRefGoogle Scholar
  25. Kreider ML, Seidler FJ, Cousins M, Tate CA, Slotkin TA (2004) Transiently overexpressed a2-adrenoceptors and their control of DNA synthesis in the developing brain. Dev Brain Res 152:233–239. CrossRefGoogle Scholar
  26. Kvetnanský R, Jahnova E, Torda T, Strbak V, Balaz V, Macho L (1978) Changes of adrenal catecholamines and their synthesizing enzymes during ontogenesis and aging in rats. Mech ageing Dev 7(3):209–216. CrossRefGoogle Scholar
  27. Lauder JM (1993) Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci 16:233–240. CrossRefGoogle Scholar
  28. Lavezzi AM, Graziella A, Luigi M (2013) Pathophysiology of the human locus coeruleus complex in fetal/neonatal sudden unexplained death. Neurol Res 35(1):44–53. CrossRefGoogle Scholar
  29. Loizou LA (1970) Uptake of monoamines into central neurons and the blood-brain barrier in the infant rat. Br J Pharmacol 40:800–813. CrossRefGoogle Scholar
  30. Marunaka Y, Niisato N, O’Brodovich H, Eaton DC (1999) Regulation of an amiloride-sensitive Na+ -permeable channel by a β2-adrenergic agonist, cytosolic Ca2+ and Clin fetal rat alveolar epithelium. J Physiol 515:669–683. CrossRefGoogle Scholar
  31. Miyaguchi H, Kato I, Sano T, Sobajima H, Fujimoto S, Togari H (1999) Dopamine penetrates to the central nervous system in developing rats. Pediatr Int 41:363–368. CrossRefGoogle Scholar
  32. Moore RY, Bloom FE (1979) Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems. Annu Rev Neurosci 2:113–168. CrossRefGoogle Scholar
  33. Murtazina AR, Nikishina YO, Bondarenko NS, Sapronova AJ, Ugrumov MV (2016) Signal molecules during the organism development: central and peripheral sources of noradrenaline in rat ontogenesis. Dokl Biochem Biophys 466(1):74–76. CrossRefGoogle Scholar
  34. Nedergaard J, Herron D, Jacobsson A, Rehnmark S, Cannon B (1995) Norepinephrine as a morphogen?: its unique interaction with brown adipose tissue. Int J Dev Biol 39:827–837Google Scholar
  35. Nguyen L, Rigo JM, Rocher V, Belachew S, Malgrange B, Rogister B, Leprince P, Moonen G (2001) Neurotransmitters as early signals for central nervous system development. Cell Tissue Res 305:187–202. CrossRefGoogle Scholar
  36. Pardridge WM (2016) CSF, blood-brain barrier, and brain drug delivery. Expert Opin Drug Deliv 13:963–975. CrossRefGoogle Scholar
  37. Pathania M, Yan LD, Bordey A (2010) A symphony of signals conducts early and late stages of adult neurogenesis. Neuropharmacology 58(6):865–876CrossRefGoogle Scholar
  38. Paxinos G, Watson C (2009) The rat brain in stereotaxic coordinates, 6th edn. Elsevier Academic Press, San DiegoGoogle Scholar
  39. Rhees RW, Shryne JE, Gorski RA (1990a) Onset of the hormone-sensitive perinatal period for sexual differentiation of the sexually dimorphic nucleus of the preoptic area in female rats. J Neurobiol 21:781–786. CrossRefGoogle Scholar
  40. Rhees RW, Shryne JE, Gorski RA (1990b) Termination of the hormone-sensitive period for differentiation of the sexually dimorphic nucleus of the preoptic area in male and female rats. Dev Brain Res 52:17–23. CrossRefGoogle Scholar
  41. Sachs C (1973) Development of the blood-brain barrier for 6-hydroxydopamine. J Neurochem 20:1753–1760. CrossRefGoogle Scholar
  42. Saunders NR, Liddelow SA, Dziegielewska KM (2012) Barrier mechanisms in the developing brain. Front Pharmacol 3:46. CrossRefGoogle Scholar
  43. Schulze C, Firth JA (1992) Interendothelial junctions during blood-brain barrier development in the rat: morphological changes at the level of individual tight junctional contacts. Dev Brain Res 69:85–95. CrossRefGoogle Scholar
  44. Simerly RB, Swanson LW, Handa RJ, Gorski RA (1985) Influence of perinatal androgen on the sexually dimorphic distribution of tyrosine hydroxylase-immunoreactive cells and fibers in the anteroventral periventricular nucleus of the rat. Neuroendocrinol 40:501–510. CrossRefGoogle Scholar
  45. Singh B, Champlain J (1972) Altered ontogenesis of central noradrenergic neurons following neonatal treatment with 6-hydroxydopamine. Brain Res 48:432–437. CrossRefGoogle Scholar
  46. Smith RD, Cooper BR, Breese GR (1973) Growth and behavioral changes in developing rats treated intracisternally ally with 6-hydroxydopamine: evidence for involvement of brain dopamine. J Pharmacol Exp Ther 185(3):609–619Google Scholar
  47. Sullivan KG, Levin M (2016) Neurotransmitter signaling pathways required for normal development in Xenopus laevis embryos: a pharmacological survey screen. J Anat 229(4):483–502CrossRefGoogle Scholar
  48. Tank WA, Wong LD (2015) Peripheral and central effects of circulating catecholamines. Compr Physiol 5:1–15. Google Scholar
  49. Teicher MH, Barber NI, Reichheld JH, Baldessarini RJ, Finklestein SP (1986) Selective depletion of cerebral norepinephrine with 6-hydroxydopamine and GBR-12909 in neonatal rat. Dev Brain Res 30:124–128. CrossRefGoogle Scholar
  50. Terasaki T, Ohtsuki S (2005) Brain-to-blood transporters for endogenous substrates and xenobiotics at the blood-brain barrier: an overview of biology and methodology. NeuroRx. 2:63–72CrossRefGoogle Scholar
  51. Thomas GB, Cummins JT, Smythe G, Gleeson RM, Dow RC, Fink G, Clarke IJ (1989) Concentrations of dopamine and noradrenaline in hypophysial portal blood in the sheep and the rat. J Endocrinol 121:141–147CrossRefGoogle Scholar
  52. Thomas SA, Matsumoto AM, Palmiter RD (1995) Noradrenaline is essential for mouse fetal development. Nature 374:643–646. CrossRefGoogle Scholar
  53. Ugrumov MV (1997) Hypothalamic monoaminergic systems in ontogenesis: development and functional significance. Int J Dev Biol 41:809–816Google Scholar
  54. Ugrumov MV (2010) Developing brain as an endocrine organ: a paradoxical reality. Neurochem Res 35:837–850. CrossRefGoogle Scholar
  55. Ugrumov MV, Ivanova IP, Mitskevich MS (1983) Permeability of the blood-brain barrier in the median eminence during the perinatal period in rats. Cell Tissue Res 230:649–660CrossRefGoogle Scholar
  56. Ugrumov MV, Sapronova AY, Melnikova VI, Proshlyakova EV, Adamskaya EI, Lavrentieva AV, Nasirova DI, Babichev VN (2005) Brain is an important source of GnRH in general circulation in the rat during prenatal and early postnatal ontogenesis. Comp Biochem Physiol A 141:271–279. CrossRefGoogle Scholar
  57. Ugrumov MV, Saifetyarova JY, Lavrentieva AV, Sapronova AY (2012) Developing brain as an endocrine organ: secretion of dopamine. Mol Cell Endocrinol 348:78–86. CrossRefGoogle Scholar
  58. Uretsky NJ, Iversen LL (1970) Effects of 6-hydroxydopamine on catecholamine containing neurones in the rat brain. J Neurochem 17(2):269–278. CrossRefGoogle Scholar
  59. Viemari JC, Bevengut M, Burnet H, Coulon P, Pequignot JM, Tiveron MC, Hilaire G (2004) Phox2a gene, A6 neurons, and noradrenaline are essential for development of normal respiratory rhythm in mice. J Neurosci 24:928–937. CrossRefGoogle Scholar
  60. Weisz J, Ward IL (1980) Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses, and neonatal offspring. Endocrinology 106:306–316. CrossRefGoogle Scholar
  61. Yokoyama C, Okamura H, Ibata Y (1993) Resistance of hypothalamic dopaminergic neurons to neonatal 6-hydroxydopamine toxicity. Brain Res Bull 30(5-6):551–559CrossRefGoogle Scholar
  62. Zubova Yu, Nasyrova D, Sapronova A, Ugrumov M (2014) Brain as an endocrine source of circulating 5-hydroxytryptamine in ontogenesis in rats. Mol Cell Endocrinol 393:92–98. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Aliia R. Murtazina
    • 1
  • Yulia O. Nikishina
    • 1
  • Nadezhda S. Bondarenko
    • 1
  • Liliya K. Dil’mukhametova
    • 1
  • Anna Ya. Sapronova
    • 1
  • Michael V. Ugrumov
    • 1
    Email author
  1. 1.Laboratory of Neural and Neuroendocrine RegulationsInstitute of Developmental Biology, Russian Academy of SciencesMoscowRussia

Personalised recommendations