Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Translational Neuroscience

Editor-in-Chief: David, Olivier

1 Issue per year

IMPACT FACTOR 2017: 0.833
5-year IMPACT FACTOR: 1.247

CiteScore 2017: 1.00

SCImago Journal Rank (SJR) 2017: 0.428
Source Normalized Impact per Paper (SNIP) 2017: 0.244

Open Access
See all formats and pricing
More options …

Astrocyte expression of D2-like dopamine receptors in the prefrontal cortex

Mihovil Mladinov
  • Department of Neuroscience, Croatian Institute for Brain Research, Zagreb University School of Medicine, Zagreb, Croatia
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Davor Mayer / Luka Brčić / Elizabeth Wolstencroft / Nguyen Man / Ian Holt / Patrick Hof / Glenn Morris / Goran Šimić
  • Department of Neuroscience, Croatian Institute for Brain Research, Zagreb University School of Medicine, Zagreb, Croatia
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2010-09-29 | DOI: https://doi.org/10.2478/v10134-010-0035-6


The dopaminergic system is of crucial importance for understanding human behavior and the pathogenesis of many psychiatric and neurological conditions. The majority of studies addressing the localization of dopamine receptors (DR) examined the expression of DR in neurons, while its expression, precise anatomical localization and possible function in glial cells have been largely neglected. Here we examined the expression of D2-like family of DR in neuronal and glial cells in the normal human brain using immunocytochemistry and immunofluorescence. Tissue samples from the right orbitomedial (Brodmann’s areas 11/12), dorsolateral (areas 9/46) and dorsal medial (area 9) prefrontal cortex were taken during autopsy from six subjects with no history of neurological or psychiatric disorders, formalin-fixed, and embedded in paraffin. The sections were stained using novel anti-DRD2, anti-DRD3, and anti-DRD4 monoclonal antibodies. Adjacent sections were labeled with an anti-GFAP (astroglial marker) and an anti-CD68 antibody (macrophage/microglial marker). The pyramidal and non-pyramidal cells of all three regions analyzed had strong expression of DRD2 and DRD4, whereas DRD3 were very weakly expressed. DRD2 were more strongly expressed in layer III compared to layer V pyramidal neurons. In contrast, DRD4 receptors had a stronger expression in layer V neurons. The most conspicuous finding was the strong expression of DRD2, but not DRD3 or DRD4, receptors in the white matter fibrous astrocytes and in layer I protoplasmic astrocytes. Weak DRD2-immunoreactivity was also observed in protoplasmic astrocytes in layers III and V. These results suggest that DR-expressing astrocytes directly participate in dopaminergic transmission of the human prefrontal cortex.

Keywords: Astrocytes; Depression; Dopamine receptors; Drug abuse; Monoclonal antibodies; Prefrontal cortex; Schizophrenia

  • [1] Winterer G., Weinberger D.R., Genes, dopamine and cortical signalto-noise ration in schizophrenia, Trends Neurosci., 2004, 27, 683–690 http://dx.doi.org/10.1016/j.tins.2004.08.002CrossrefGoogle Scholar

  • [2] Arrias-Carrión O., Poppel E., Dopamine, learning, and reward-seeking behavior, Acta Neurobiol. Exp., 2007, 67, 481–488 Google Scholar

  • [3] Šešo-Šimić Đ., Sedmak G., Hof P.R., Šimić G., Recent advances in the neurobiology of attachment behavior, Transl. Neurosci., 2010, 2, 148–159 Web of ScienceGoogle Scholar

  • [4] Gaspar P., Berger B., Febvret A., Vigny A., Henry J.P., Catecholamine innervation of the human cerebral cortex as revealed by comparative immunohistochemistry of tyrosine hydroxylase and dopamine-beta-hydroxylase, J. Comp. Neurol., 1989, 279, 249–271 http://dx.doi.org/10.1002/cne.902790208CrossrefGoogle Scholar

  • [5] Raghanti M.A., Stimpson C.D., Marcinkiewicz J.L., Erwin J.M., Hof P.R., Sherwood C.C., Cortical dopaminergic innervation among humans, chimpanzees, and macaque monkeys: a comparative study, Neuroscience, 2008, 155, 203–220 http://dx.doi.org/10.1016/j.neuroscience.2008.05.008Web of ScienceCrossrefGoogle Scholar

  • [6] Lewis D.A., Melchitzky D.S., Sesack S.R., Whitehead R.E., Auh S., Sampson A., Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization, J. Comp. Neurol., 2001, 432, 119–136 http://dx.doi.org/10.1002/cne.1092CrossrefGoogle Scholar

  • [7] Björklund A., Dunnet S.B., Dopamine neuron systems in the brain: an update, Trends Neurosci., 2007, 30, 194–202 http://dx.doi.org/10.1016/j.tins.2007.03.006Web of ScienceCrossrefGoogle Scholar

  • [8] Seeman P., Dopamine receptor sequences: therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4, Neuropsychopharmacology, 1992, 7, 261–284 Google Scholar

  • [9] Mrzljak L., Bergson C., Pappy M., Huff R., Levenson R., Goldman-Rakic P.S., Localization of dopamine D4 receptors in GABAergic neurons of the primate brain, Nature, 1996, 381, 245–248 http://dx.doi.org/10.1038/381245a0CrossrefGoogle Scholar

  • [10] Sokoloff P., Giros B., Martres M.P., Bouthenet M.L., Schwartz J.C., Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics, Nature, 1990, 347, 146–151 http://dx.doi.org/10.1038/347146a0CrossrefGoogle Scholar

  • [11] Suzuki M., Hurd Y.L., Sokoloff P., Schwartz J.C., Sedvall G., D3 dopamine receptor mRNA is widely expressed in the human brain, Brain Res., 1998, 779, 58–74 http://dx.doi.org/10.1016/S0006-8993(97)01078-0CrossrefGoogle Scholar

  • [12] Hurd Y.L., Suzuki M., Sedvall G., D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain, J. Chem. Neuroanat., 2001, 22, 127–137 http://dx.doi.org/10.1016/S0891-0618(01)00122-3CrossrefGoogle Scholar

  • [13] Martres M.P., Bouthenet M.L., Sales N., Sokoloff P., Schwartz J.C., Widespread distribution of brain dopamine receptors evidenced with [125I]iodosulpride, a highly selective ligand, Science, 1985, 228, 752–755 http://dx.doi.org/10.1126/science.3838821CrossrefGoogle Scholar

  • [14] Camps M., Cortes R., Gueye B., Probst A., Palacios J.M., Dopamine receptors in human brain: autoradiographic distribution of D2R sites, Neuroscience, 1989, 28, 275–90 http://dx.doi.org/10.1016/0306-4522(89)90179-6CrossrefGoogle Scholar

  • [15] Lidow M.S., Goldman-Rakic P.S., Rakic P., Innis R.B., Dopamine D2 receptors in the cerebral cortex: distribution and pharmacological characterization with [3H] raclopride, Proc. Natl. Acad. Sci. USA, 1989, 86, 6412–6416 http://dx.doi.org/10.1073/pnas.86.16.6412CrossrefGoogle Scholar

  • [16] Lidow M.S., Goldman-Rakic P.S., Gallager D.W., Rakic P., Distribution of dopaminergic receptors in the primate cerebral cortex: Quantitative autoradiographic analysis using [3H]raclopride, [3H]spiperone and [3H]SCH23390, Neuroscience, 1991, 40, 657–671 http://dx.doi.org/10.1016/0306-4522(91)90003-7CrossrefGoogle Scholar

  • [17] Levant B., Differential distribution of D3 dopamine receptors in the brains of several mammalian species, Brain Res., 1998, 800, 269–274 http://dx.doi.org/10.1016/S0006-8993(98)00529-0CrossrefGoogle Scholar

  • [18] Paspalas C.D., Goldman-Rakic P.S., Microdomains for dopamine volume neurotransmission in primate prefrontal cortex, J. Neurosci., 2004, 24, 5292–5300 http://dx.doi.org/10.1523/JNEUROSCI.0195-04.2004CrossrefGoogle Scholar

  • [19] Khan Z.U., Gutierrez A., Martin R., Penafiel A., Rivera A., De La Calle A., Differential regional and cellular distribution of dopamine D2-like receptors: an immunocytochemical study of subtype-specific antibodies in rat and human brain, J. Comp. Neurol., 1998, 402, 353–371 http://dx.doi.org/10.1002/(SICI)1096-9861(19981221)402:3<353::AID-CNE5>3.0.CO;2-4CrossrefGoogle Scholar

  • [20] Khan Z.U., Koulen P., Rubinstein M., Grandy D.K., Goldman-Rakic P.S., An astroglia-linked dopamine D2-receptor action in prefrontal cortex, Proc. Natl. Acad. Sci. USA, 2001, 98, 1964–1969 http://dx.doi.org/10.1073/pnas.98.4.1964CrossrefGoogle Scholar

  • [21] Negyessy L., Goldman-Rakic P.S., Subcellular localization of the dopamine D2 receptor and coexistence with the calcium-binding protein neuronal calcium sensor-1 in the primate prefrontal cortex, J. Comp. Neurol., 2005, 488, 464–475 http://dx.doi.org/10.1002/cne.20601Google Scholar

  • [22] Gaspar P., Bloch B., Le Moine C., D1 and D2 receptor gene expression in the rat frontal cortex: cellular localization in different classes of efferent neurons, Eur. J. Neurosci., 1995, 7, 1050–1063 http://dx.doi.org/10.1111/j.1460-9568.1995.tb01092.xCrossrefGoogle Scholar

  • [23] Meador-Woodruff J.H., Damask S.P., Wang J., Haroutunian V., Davis K.L., Watson S.J., Dopamine receptor mRNA expression in human striatum and neocortex, Neuropsychopharmacology, 1996, 15, 17–29 http://dx.doi.org/10.1016/0893-133X(95)00150-CCrossrefGoogle Scholar

  • [24] Henn F.A., Anderson D.J., Sellström, Å., Possible relationship between glial cells, dopamine and the effects of antipsychotic drugs, Nature, 1977, 266, 637–638 http://dx.doi.org/10.1038/266637a0CrossrefGoogle Scholar

  • [25] Miyazaki I., Asanuma M., Diaz-Corrales F.J., Miyoshi K., Ogawa N., Direct evidence for expression of dopamine receptors in astrocytes from basal ganglia, Brain Res., 2004, 1029, 120–123 http://dx.doi.org/10.1016/j.brainres.2004.09.014CrossrefGoogle Scholar

  • [26] Kumar U., Patel S.C., Immunohistochemical localization of dopamine receptor subtypes (D1R-D5R) in Alzheimer’s disease brain, Brain. Res., 2007, 1131, 187–196 http://dx.doi.org/10.1016/j.brainres.2006.10.049Web of ScienceGoogle Scholar

  • [27] Beazely M.A., Tong A., Wei W.L., Van Tol H., Sidhu B., MacDonald J.F., D2-class dopamine receptor inhibition of NMDA currents in prefrontal cortical neurons is platelet-derived growth factor receptor-dependent, J. Neurochem., 2006, 98, 1657–1663 http://dx.doi.org/10.1111/j.1471-4159.2006.04064.xCrossrefGoogle Scholar

  • [28] Wolstencroft E.C., Simic G., thi Man N, Holt I, Lam LT, Buckland P.R. et al., Endosomal location of dopamine receptors in neuronal cell cytoplasm, J. Mol. Histol., 2007, 38, 333–340 http://dx.doi.org/10.1007/s10735-007-9106-5CrossrefGoogle Scholar

  • [29] Lewis D.A., Campbell M.J., Foote S.L., Morrison J.H., The monoaminergic innervation of primate neocortex, Hum. Neurobiol., 1986, 5, 181–188 Google Scholar

  • [30] Lewis D.A., Campbell M.J., Foote S.L., Goldstein M., Morrison J.H., The distribution of tyrosine hydroxylase-immunoreactive fibers in primate neocortex is widespread but regionally specific, J. Neurosci., 1987, 7, 279–290 Google Scholar

  • [31] Lewis D.A., Foote S.L., Goldstein M., Morrison J.H., The dopaminergic innervation of monkey prefrontal cortex: a tyrosine hydroxylase immunohistochemical study, Brain Res., 1988, 449, 225–243 http://dx.doi.org/10.1016/0006-8993(88)91040-2CrossrefGoogle Scholar

  • [32] Berger B., Gaspar P., Verney C., Dopaminergic innervation of the cerebral cortex: unexpected differences between rodent and primate, Trends Neurosci., 1991, 14, 21–27 http://dx.doi.org/10.1016/0166-2236(91)90179-XCrossrefGoogle Scholar

  • [33] Halliday G.M., Törk I., Comparative anatomy of the ventromedial mesencephalic tegmentum in the rat, cat, monkey and human, J. Comp. Neurol., 1986, 252, 423–445 http://dx.doi.org/10.1002/cne.902520402CrossrefGoogle Scholar

  • [34] Goldman-Rakic P.S., Lidow M.S., Gallagher D.W., Overlap of dopaminergic, adrenergic, and serotoninergic receptors and complementarity of their subtypes in primate prefrontal cortex, J. Neurosci., 1990, 10, 2125–2138 Google Scholar

  • [35] Goldman-Rakic P.S., Leranth C., Williams S.M., Mons N., Geffard M., Dopamine synaptic complex with pyramidal neurons in primate cerebral cortex, Proc. Natl. Acad. Sci. USA, 1989, 86, 9015–9019 http://dx.doi.org/10.1073/pnas.86.22.9015CrossrefGoogle Scholar

  • [36] Berger B., Trottier S., Verney C., Gaspar P., Alvarez A., Regional and laminar distribution of the dopamine and serotonin innervation in the macaque cerebral cortex: a radioautographic study, J. Comp. Neurol., 1988, 273, 99–119 http://dx.doi.org/10.1002/cne.902730109CrossrefGoogle Scholar

  • [37] Berger B., Verney C., Goldman-Rakic P.S., Prenatal monoaminergic innervation of the cerebral cortex: differences between rodents and primates. In: Neurodevelopment, Aging and Cognition (eds. Kostović I, Knežević S, Wisniewski HM, Spilich GJ), Birkhuser: Boston, Basel, Berlin, 1992, 18–36 Google Scholar

  • [38] Campbell M.J., Lewis D.A., Foote S.L., Morrison J.H., Distribution of choline acetyltransferase-, serotonin-, dopamine-beta-hydroxylase-, tyrosine hydroxylase-immunoreactive fibers in monkey primary auditory cortex, J. Comp. Neurol., 1987, 261, 209–220 http://dx.doi.org/10.1002/cne.902610204CrossrefGoogle Scholar

  • [39] Foote S.L., Morrison J.H., Extrathalamic modulation of cortical function. Annu. Rev. Neurosci., 1987, 10, 67–95 http://dx.doi.org/10.1146/annurev.ne.10.030187.000435CrossrefGoogle Scholar

  • [40] Dorus S., Vallender E.J., Evans P.D., Anderson J.R., Gilbert S.L., Mahowald M., et al., Accelerated evolution of nervous system genes in the origin of Homo sapiens, Cell, 2004, 119, 1027–1040 http://dx.doi.org/10.1016/j.cell.2004.11.040CrossrefGoogle Scholar

  • [41] Akil M., Pierri J.N., Whitehead R.E., Edgar C.L., Mohila C., Sampson A.R. et al., Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic patients, Am. J. Psychiatry, 1999, 156, 1580–1589 Google Scholar

  • [42] Reuss B., Unsicker K., Survival and differentiation of dopaminergic mesencephalic neurons are promoted by dopamine-mediated induction of FGF-2 in striatal astroglial cells, Mol. Cell. Neurosci., 2000, 16, 781–792 http://dx.doi.org/10.1006/mcne.2000.0906CrossrefGoogle Scholar

  • [43] Ohta K., Kuno S., Inoue S., Ikeda E, Fujinami A, Ohta M., The effect of dopamine agonists: the expression of GDNF, NGF, and BDNF in cultured mouse astrocytes, J. Neurol. Sci., 2010, 291, 12–16 http://dx.doi.org/10.1016/j.jns.2010.01.013CrossrefWeb of ScienceGoogle Scholar

  • [44] Reuss B., Unsicker K., Atypical neuroleptic drugs downregulate dopamine sensitivity in rat cortical and striatal astrocytes, Mol. Cell. Neurosci., 2001, 18, 197–209 http://dx.doi.org/10.1006/mcne.2001.1017CrossrefGoogle Scholar

About the article

Published Online: 2010-09-29

Published in Print: 2010-09-01

Citation Information: Translational Neuroscience, Volume 1, Issue 3, Pages 238–243, ISSN (Online) 2081-6936, ISSN (Print) 2081-3856, DOI: https://doi.org/10.2478/v10134-010-0035-6.

Export Citation

© 2010 Versita Warsaw. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. BY-NC-ND 3.0

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Alexei Verkhratsky and Maiken Nedergaard
Physiological Reviews, 2018, Volume 98, Number 1, Page 239
Sanhita Sinharay, Dianne Lee, Swati Shah, Siva Muthusamy, Georgios Z. Papadakis, Xiang Zhang, Dragan Maric, William C. Reid, and Dima A. Hammoud
Nuclear Medicine and Biology, 2017
Goran Šimić, Mirjana Babić Leko, Selina Wray, Charles R. Harrington, Ivana Delalle, Nataša Jovanov-Milošević, Danira Bažadona, Luc Buée, Rohan de Silva, Giuseppe Di Giovanni, Claude M. Wischik, and Patrick R. Hof
Progress in Neurobiology, 2017, Volume 151, Page 101
Božo Krušlin, Tihana Džombeta, Miran Bezjak, Goran Sedmak, Zdravko Petanjek, Goran Šimić, Miloš Judaš, and Ivica Kostović
Translational Neuroscience, 2014, Volume 5, Number 4
Miloš Judaš, Goran Šimić, Zdravko Petanjek, Nataša Jovanov-Milošević, Mihovil Pletikos, Lana Vasung, Mario Vukšić, and Ivica Kostović
Annals of the New York Academy of Sciences, 2011, Volume 1225, Number S1, Page E105

Comments (0)

Please log in or register to comment.
Log in