Skip to main content
SpringerLink
Log in

Regional Characteristics of Histamine Uptake into Neonatal Rat Astrocytes

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Histaminergic signalling constitutes an attractive target for treatment of neuropsychiatric disorders. One obstacle to developing new pharmacological options has been failure to identify putative specific histamine transporter responsible for histamine clearance. Although high-affinity histamine uptake was detected in neonatal cortical astrocytes, its existence in other brain regions remains largely unexplored. We investigated whether cerebellar and striatal astrocytes participate in histamine clearance and evaluated the role of organic cation transporters (OCT) in astroglial histamine transport. Kinetic and pharmacological characteristics of histamine transport were determined in cultured astrocytes derived from neonatal rat cerebellum, striatum and cerebral cortex. As well as astrocytes of cortical origin, cultured striatal and cerebellar astrocytes displayed temperature-sensitive, high-affinity histamine uptake. Exposure to ouabain or Na+-free medium, supplemented with choline chloride markedly depressed histamine transport in cortical astrocytes. Conversely, histamine uptake in striatal and cortical astrocytes was ouabain-resistant and was only partially diminished during incubation in the absence of Na+. Also, histamine uptake remained unaltered upon exposure to OCT inhibitor corticosterone, although OCTs were expressed in cultured astrocytes. Finally, histamine transport in cerebellar and striatal astrocytes was not sensitive to antidepressants. Despite common characteristics, cerebellar astrocytes had lower affinity, but markedly higher transport capacity for histamine compared to striatal astrocytes. Collectively, we provide evidence to suggest that cerebellar, striatal as well as cortical astrocytes possess saturable histamine uptake systems, which are not operated by OCTs. In addition, our data indicate that Na+-independent histamine carrier predominates in cerebellar and striatal astrocytes, whereas Na+-dependent transporter underlies histamine uptake in cortical astrocytes. Our findings implicate a role for histamine transporters in regulation of extracellular histamine concentration in cerebellum and striatum. Inhibition of histamine uptake might represent a viable option to modulate histaminergic neurotransmission.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Haas HL, Sergeeva OA, Selbach O (2008) Histamine in the nervous system. Physiol Rev 88(3):1183–1241. doi:10.1152/physrev.00043.2007

    Article  PubMed  CAS  Google Scholar 

  2. Passani MB, Blandina P (2011) Histamine receptors in the CNS as targets for therapeutic intervention. Trends Pharmacol Sci 32(4):242–249. doi:10.1016/j.tips.2011.01.003

    Article  PubMed  CAS  Google Scholar 

  3. Iversen L (2006) Neurotransmitter transporters and their impact on the development of psychopharmacology. Br J Pharmacol 147(Suppl 1):S82–S88. doi:10.1038/sj.bjp.0706428

    PubMed  CAS  Google Scholar 

  4. Schwartz JC, Arrang JM, Garbarg M, Pollard H, Ruat M (1991) Histaminergic transmission in the mammalian brain. Physiol Rev 71(1):1–51

    PubMed  CAS  Google Scholar 

  5. Haas H, Panula P (2003) The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci 4(2):121–130. doi:10.1038/nrn1034

    Article  PubMed  CAS  Google Scholar 

  6. Merickel A, Edwards RH (1995) Transport of histamine by vesicular monoamine transporter-2. Neuropharmacology 34(11):1543–1547

    Article  PubMed  CAS  Google Scholar 

  7. Sakurai E, Oreland L, Nishiyama S, Kato M, Watanabe T, Yanai K (2006) Evidence for the presence of histamine uptake into the synaptosomes of rat brain. Pharmacology 78(2):72–80. doi:10.1159/000095637

    Article  PubMed  CAS  Google Scholar 

  8. Barnes WG, Hough LB (2002) Membrane-bound histamine N-methyltransferase in mouse brain: possible role in the synaptic inactivation of neuronal histamine. J Neurochem 82(5):1262–1271

    Article  PubMed  CAS  Google Scholar 

  9. Rafalowska U, Waskiewicz J, Albrecht J (1987) Is neurotransmitter histamine predominantly inactivated in astrocytes? Neurosci Lett 80(1):106–110

    Article  PubMed  CAS  Google Scholar 

  10. Huszti Z, Imrik P, Madarasz E (1994) [3H]histamine uptake and release by astrocytes from rat brain: effects of sodium deprivation, high potassium, and potassium channel blockers. Neurochem Res 19(10):1249–1256

    Article  PubMed  CAS  Google Scholar 

  11. Huszti Z, Rimanoczy A, Juhasz A, Magyar K (1990) Uptake, metabolism, and release of [3H]-histamine by glial cells in primary cultures of chicken cerebral hemispheres. Glia 3(3):159–168. doi:10.1002/glia.440030303

    Article  PubMed  CAS  Google Scholar 

  12. Osredkar D, Burnik-Papler T, Pecavar B, Kralj-Iglic V, Krzan M (2009) Kinetic and pharmacological properties of [(3)H]-histamine transport into cultured type 1 astrocytes from neonatal rats. Inflamm Res 58(2):94–102. doi:10.1007/s00011-009-8103-4

    Article  PubMed  CAS  Google Scholar 

  13. Perdan-Pirkmajer K, Pirkmajer S, Cerne K, Krzan M (2012) Molecular and kinetic characterization of histamine transport into adult rat cultured astrocytes. Neurochem Int 61(3):415–422. doi:10.1016/j.neuint.2012.05.002

    Article  PubMed  CAS  Google Scholar 

  14. Perdan-Pirkmajer K, Mavri J, Krzan M (2010) Histamine (re)uptake by astrocytes: an experimental and computational study. J Mol Model 16(6):1151–1158. doi:10.1007/s00894-009-0624-9

    Article  PubMed  CAS  Google Scholar 

  15. Huszti Z, Magyar K, Kalman M (1990) Contribution of glial cells to histamine inactivation. Agents Actions 30(1–2):237–239

    Article  PubMed  CAS  Google Scholar 

  16. Huszti Z, Prast H, Tran MH, Fischer H, Philippu A (1998) Glial cells participate in histamine inactivation in vivo. Naunyn Schmiedebergs Arch Pharmacol 357(1):49–53

    Article  PubMed  CAS  Google Scholar 

  17. Baganz NL, Horton RE, Calderon AS, Owens WA, Munn JL, Watts LT, Koldzic-Zivanovic N, Jeske NA, Koek W, Toney GM, Daws LC (2008) Organic cation transporter 3: keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice. Proc Natl Acad Sci USA 105(48):18976–18981. doi:10.1073/pnas.0800466105

    Article  PubMed  CAS  Google Scholar 

  18. Pickel VM, Chan J (1999) Ultrastructural localization of the serotonin transporter in limbic and motor compartments of the nucleus accumbens. J Neurosci 19(17):7356–7366

    PubMed  CAS  Google Scholar 

  19. Takeda H, Inazu M, Matsumiya T (2002) Astroglial dopamine transport is mediated by norepinephrine transporter. Naunyn Schmiedebergs Arch Pharmacol 366(6):620–623. doi:10.1007/s00210-002-0640-0

    Article  PubMed  CAS  Google Scholar 

  20. Giros B, el Mestikawy S, Bertrand L, Caron MG (1991) Cloning and functional characterization of a cocaine-sensitive dopamine transporter. FEBS Lett 295(1–3):149–154

    Article  PubMed  CAS  Google Scholar 

  21. Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD (1993) Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci USA 90(6):2542–2546

    Article  PubMed  CAS  Google Scholar 

  22. Demchyshyn LL, Pristupa ZB, Sugamori KS, Barker EL, Blakely RD, Wolfgang WJ, Forte MA, Niznik HB (1994) Cloning, expression, and localization of a chloride-facilitated, cocaine-sensitive serotonin transporter from Drosophila melanogaster. Proc Natl Acad Sci USA 91(11):5158–5162

    Article  PubMed  CAS  Google Scholar 

  23. Gasser PJ, Lowry CA, Orchinik M (2006) Corticosterone-sensitive monoamine transport in the rat dorsomedial hypothalamus: potential role for organic cation transporter 3 in stress-induced modulation of monoaminergic neurotransmission. J Neurosci 26(34):8758–8766. doi:10.1523/JNEUROSCI.0570-06.2006

    Article  PubMed  CAS  Google Scholar 

  24. Baganz N, Horton R, Martin K, Holmes A, Daws LC (2010) Repeated swim impairs serotonin clearance via a corticosterone-sensitive mechanism: organic cation transporter 3, the smoking gun. J Neurosci 30(45):15185–15195. doi:10.1523/JNEUROSCI.2740-10.2010

    Article  PubMed  CAS  Google Scholar 

  25. Grundemann D, Liebich G, Kiefer N, Koster S, Schomig E (1999) Selective substrates for non-neuronal monoamine transporters. Mol Pharmacol 56(1):1–10

    PubMed  CAS  Google Scholar 

  26. Schomig E, Lazar A, Grundemann D (2006) Extraneuronal monoamine transporter and organic cation transporters 1 and 2: a review of transport efficiency. Handb Exp Pharmacol 175:151–180

    Article  PubMed  Google Scholar 

  27. Amphoux A, Vialou V, Drescher E, Bruss M, Mannoury La Cour C, Rochat C, Millan MJ, Giros B, Bonisch H, Gautron S (2006) Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology 50(8):941–952. doi:10.1016/j.neuropharm.2006.01.005

    Article  PubMed  CAS  Google Scholar 

  28. Duan H, Wang J (2010) Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther 335(3):743–753. doi:10.1124/jpet.110.170142

    Article  PubMed  CAS  Google Scholar 

  29. Cui M, Aras R, Christian WV, Rappold PM, Hatwar M, Panza J, Jackson-Lewis V, Javitch JA, Ballatori N, Przedborski S, Tieu K (2009) The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway. Proc Natl Acad Sci USA 106(19):8043–8048. doi:10.1073/pnas.0900358106

    Article  PubMed  CAS  Google Scholar 

  30. Gasser PJ, Orchinik M, Raju I, Lowry CA (2009) Distribution of organic cation transporter 3, a corticosterone-sensitive monoamine transporter, in the rat brain. J Comp Neurol 512(4):529–555. doi:10.1002/cne.21921

    Article  PubMed  CAS  Google Scholar 

  31. Zhu P, Hata R, Ogasawara M, Cao F, Kameda K, Yamauchi K, Schinkel AH, Maeyama K, Sakanaka M (2012) Targeted disruption of organic cation transporter 3 (Oct3) ameliorates ischemic brain damage through modulating histamine and regulatory T cells. J Cereb Blood Flow Metab 32(10):1897–1908. doi:10.1038/jcbfm.2012.92

    Article  PubMed  CAS  Google Scholar 

  32. Vialou V, Balasse L, Callebert J, Launay JM, Giros B, Gautron S (2008) Altered aminergic neurotransmission in the brain of organic cation transporter 3-deficient mice. J Neurochem 106(3):1471–1482. doi:10.1111/j.1471-4159.2008.05506.x

    PubMed  CAS  Google Scholar 

  33. Krzan M, Schwartz JP (2006) Histamine transport in neonatal and adult astrocytes. Inflamm Res 55(Suppl 1):S36–S37. doi:10.1007/s00011-005-0031-3

    Article  PubMed  CAS  Google Scholar 

  34. Schwartz JP, Wilson DJ (1992) Preparation and characterization of type 1 astrocytes cultured from adult rat cortex, cerebellum, and striatum. Glia 5(1):75–80. doi:10.1002/glia.440050111

    Article  PubMed  CAS  Google Scholar 

  35. Tuomi JM, Voorbraak F, Jones DL, Ruijter JM (2010) Bias in the Cq value observed with hydrolysis probe based quantitative PCR can be corrected with the estimated PCR efficiency value. Methods 50(4):313–322. doi:10.1016/j.ymeth.2010.02.003

    Article  PubMed  CAS  Google Scholar 

  36. Rose CR, Waxman SG, Ransom BR (1998) Effects of glucose deprivation, chemical hypoxia, and simulated ischemia on Na+ homeostasis in rat spinal cord astrocytes. J Neurosci 18(10):3554–3562

    PubMed  CAS  Google Scholar 

  37. Chibalin AV, Heiny JA, Benziane B, Prokofiev AV, Vasiliev AV, Kravtsova VV, Krivoi II (2012) Chronic nicotine modifies skeletal muscle Na, K-ATPase activity through its interaction with the nicotinic acetylcholine receptor and phospholemman. PLoS ONE 7(3):e33719. doi:10.1371/journal.pone.0033719

    Article  PubMed  CAS  Google Scholar 

  38. Dahlin A, Xia L, Kong W, Hevner R, Wang J (2007) Expression and immunolocalization of the plasma membrane monoamine transporter in the brain. Neuroscience 146(3):1193–1211. doi:10.1016/j.neuroscience.2007.01.072

    Article  PubMed  CAS  Google Scholar 

  39. Daws LC (2009) Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy. Pharmacol Ther 121(1):89–99. doi:10.1016/j.pharmthera.2008.10.004

    Article  PubMed  CAS  Google Scholar 

  40. Wu X, Kekuda R, Huang W, Fei YJ, Leibach FH, Chen J, Conway SJ, Ganapathy V (1998) Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem 273(49):32776–32786

    Article  PubMed  CAS  Google Scholar 

  41. Arndt P, Volk C, Gorboulev V, Budiman T, Popp C, Ulzheimer-Teuber I, Akhoundova A, Koppatz S, Bamberg E, Nagel G, Koepsell H (2001) Interaction of cations, anions, and weak base quinine with rat renal cation transporter rOCT2 compared with rOCT1. Am J Physiol Renal Physiol 281(3):F454–F468

    PubMed  CAS  Google Scholar 

  42. Hayer-Zillgen M, Bruss M, Bonisch H (2002) Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br J Pharmacol 136(6):829–836. doi:10.1038/sj.bjp.0704785

    Article  PubMed  CAS  Google Scholar 

  43. Perdan K, Kobe Z, Krzan M (2009) Nature of histamine transport in neonatal rat cultured type 1 astrocytes–organic cation transporters are not involved. Inflamm Res 58(Suppl 1):32–33. doi:10.1007/s00011-009-0655-9

    Article  PubMed  Google Scholar 

  44. Huszti Z (1998) Carrier-mediated high affinity uptake system for histamine in astroglial and cerebral endothelial cells. J Neurosci Res 51(5):551–558. doi:10.1002/(SICI)1097-4547(19980301)51:5<551:AID-JNR1>3.0.CO;2-E

    Article  PubMed  CAS  Google Scholar 

  45. Huszti Z (2003) Histamine uptake into non-neuronal brain cells. Inflamm Res 52(Suppl 1):S03–S06

    Article  PubMed  Google Scholar 

  46. Giannoni P, Passani MB, Nosi D, Chazot PL, Shenton FC, Medhurst AD, Munari L, Blandina P (2009) Heterogeneity of histaminergic neurons in the tuberomammillary nucleus of the rat. Eur J Neurosci 29(12):2363–2374. doi:10.1111/j.1460-9568.2009.06765.x

    Article  PubMed  Google Scholar 

  47. Rinne JO, Anichtchik OV, Eriksson KS, Kaslin J, Tuomisto L, Kalimo H, Roytta M, Panula P (2002) Increased brain histamine levels in Parkinson’s disease but not in multiple system atrophy. J Neurochem 81(5):954–960

    Article  PubMed  CAS  Google Scholar 

  48. Carfagna MA, Muhoberac BB (1993) Interaction of tricyclic drug analogs with synaptic plasma membranes: structure-mechanism relationships in inhibition of neuronal Na+/K(+)-ATPase activity. Mol Pharmacol 44(1):129–141

    PubMed  CAS  Google Scholar 

  49. Sanganahalli BG, Joshi PG, Joshi NB (2000) Differential effects of tricyclic antidepressant drugs on membrane dynamics–a fluorescence spectroscopic study. Life Sci 68(1):81–90

    Article  PubMed  CAS  Google Scholar 

  50. Sweet DH, Miller DS, Pritchard JB (2001) Ventricular choline transport: a role for organic cation transporter 2 expressed in choroid plexus. J Biol Chem 276(45):41611–41619. doi:10.1074/jbc.M108472200

    Article  PubMed  CAS  Google Scholar 

  51. Koepsell H, Lips K, Volk C (2007) Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 24(7):1227–1251. doi:10.1007/s11095-007-9254-z

    Article  PubMed  CAS  Google Scholar 

  52. Engel K, Wang J (2005) Interaction of organic cations with a newly identified plasma membrane monoamine transporter. Mol Pharmacol 68(5):1397–1407. doi:10.1124/mol.105.016832

    Article  PubMed  CAS  Google Scholar 

  53. Engel K, Zhou M, Wang J (2004) Identification and characterization of a novel monoamine transporter in the human brain. J Biol Chem 279(48):50042–50049. doi:10.1074/jbc.M407913200

    Article  PubMed  CAS  Google Scholar 

  54. Vialou V, Balasse L, Dumas S, Giros B, Gautron S (2007) Neurochemical characterization of pathways expressing plasma membrane monoamine transporter in the rat brain. Neuroscience 144(2):616–622. doi:10.1016/j.neuroscience.2006.09.058

    Article  PubMed  CAS  Google Scholar 

  55. Inazu M, Takeda H, Maehara K, Miyashita K, Tomoda A, Matsumiya T (2006) Functional expression of the organic cation/carnitine transporter 2 in rat astrocytes. J Neurochem 97(2):424–434. doi:10.1111/j.1471-4159.2006.03757.x

    Article  PubMed  CAS  Google Scholar 

  56. Inazu M, Takeda H, Matsumiya T (2005) Molecular and functional characterization of an Na + -independent choline transporter in rat astrocytes. J Neurochem 94(5):1427–1437. doi:10.1111/j.1471-4159.2005.03299.x

    Article  PubMed  CAS  Google Scholar 

  57. Ohashi R, Tamai I, Nezu Ji J, Nikaido H, Hashimoto N, Oku A, Sai Y, Shimane M, Tsuji A (2001) Molecular and physiological evidence for multifunctionality of carnitine/organic cation transporter OCTN2. Mol Pharmacol 59(2):358–366

    PubMed  CAS  Google Scholar 

  58. Codeluppi S, Gregory EN, Kjell J, Wigerblad G, Olson L, Svensson CI (2011) Influence of rat substrain and growth conditions on the characteristics of primary cultures of adult rat spinal cord astrocytes. J Neurosci Methods 197(1):118–127. doi:10.1016/j.jneumeth.2011.02.011

    Article  PubMed  Google Scholar 

  59. Kimelberg HK, Goderie SK, Conley PA, Higman S, Goldschmidt R, Amundson RH (1992) Uptake of [3H]serotonin and [3H]glutamate by primary astrocyte cultures. I. Effects of different sera and time in culture. Glia 6 (1):1–8. doi:10.1002/glia.440060102

    Google Scholar 

  60. Amundson RH, Goderie SK, Kimelberg HK (1992) Uptake of [3H]serotonin and [3H]glutamate by primary astrocyte cultures. II. Differences in cultures prepared from different brain regions. Glia 6(1):9–18. doi:10.1002/glia.440060103

    Google Scholar 

  61. Molina-Hernandez A, Diaz NF, Arias-Montano JA (2012) Histamine in brain development. J Neurochem 122(5):872–882. doi:10.1111/j.1471-4159.2012.07863.x

    Article  PubMed  CAS  Google Scholar 

  62. Nishibori M, Oishi R, Saeki K (1984) Histamine turnover in the brain of different mammalian species: implications for neuronal histamine half-life. J Neurochem 43(6):1544–1549

    Article  PubMed  CAS  Google Scholar 

  63. Oishi R, Nishibori M, Saeki K (1984) Regional differences in the turnover of neuronal histamine in the rat brain. Life Sci 34(7):691–699

    Article  PubMed  CAS  Google Scholar 

  64. Hough LB, Khandelwal JK, Green JP (1984) Histamine turnover in regions of rat brain. Brain Res 291(1):103–109

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the research grant P3-067, J1-2014 of Ministry of Higher Education, Science and Technology, Republic of Slovenia. We greatly appreciate technical assistance of Mrs Jožica Košir.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1001, Ljubljana, Slovenia

    Katja Perdan-Pirkmajer, Andreja Raztresen & Mojca Krzan

  2. Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Zaloska 4, 1001, Ljubljana, Slovenia

    Sergej Pirkmajer

Authors
  1. Katja Perdan-Pirkmajer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sergej Pirkmajer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andreja Raztresen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mojca Krzan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mojca Krzan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Perdan-Pirkmajer, K., Pirkmajer, S., Raztresen, A. et al. Regional Characteristics of Histamine Uptake into Neonatal Rat Astrocytes. Neurochem Res 38, 1348–1359 (2013). https://doi.org/10.1007/s11064-013-1028-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-013-1028-x

Keywords

Search

Navigation