Bimodal Distribution of Brain Dopamine D2 Receptors in Schizophrenic Patients Explained by In Vivo Binding Studies

  • J. Korf
  • S. Zijlstra
  • J. A. A. Swart
  • J. W. Louwerens
Conference paper


The so-called dopamine bypothesis in schizophrenia can be divided into two subhypotheses: one involving pathogenetic aspects of the dopamine systems in the brain and the other the mode of action of antipsychotic drugs (Carlsson 1988). In particular, the D2 type dopamine receptor has been studied both in vitro (e.g., Seeman et al. 1984, 1987; Kornhuber et al. 1989) and very recently in vivo (e.g., Wong et al. 1986; Farde et al. 1987, 1988; Sedvall et al. 1986). Reports showing a pathogenetically increased dopamine D2 type receptor density in vivo (e.g., Seeman et al. 1984, 1987; Kornhuber et al. 1989, and references therein) have been challenged as being the result of long-term antipsychotic medication (e.g., Kornhuber et al. 1989). In the most extensive report on in vitro D2 receptor investigations, published by Seeman and collaborators (1984, 1987), more than 100 schizophrenic brain specimens were analyzed. There appeared to be a bimodal distribution in the density in three brain areas: caudate nucleus and putamen, structures belonging to the extrapyramidal system, and the nucleus accumbens, a limbic structure. Interestingly, the mean densities of the two modes differed by twofold and the lowest density was rather similar to that of controls or of nonschizophrenic patients treated with antipsychotic medication.


Positron Emission Tomography Dopamine Receptor Schizophrenic Patient Neuroleptic Treatment Acetylcholine Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Baron JC, Martinot JL, Cambon H, Boulenger JP, Poirer MF, Blin J, Huret JD, Loc’h C, Maziere B (1989) Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacology 99:463PubMedCrossRefGoogle Scholar
  2. Battaglia G, Titeler M (1982) [3H]n-propylapomorphine and [3H]spiperone binding in brain indicate two states of the D2-dopamine receptor. Eur J Pharmacol 81:493PubMedCrossRefGoogle Scholar
  3. Carlsson A (1988) The current status of the dopamine receptor hypothesis of schizophrenia. Neuropsychopharmacology 1:179PubMedCrossRefGoogle Scholar
  4. Coppens HJ, Slooff CJ, Paans AMJ, Wiegman T, Vaalburg W, Korf J (1991) High central D2-dopamine receptor occupancy as assessed with positron emission tomography in medicated but therapy resistant schizophrenic patients. Biol Psychiatry 29:429CrossRefGoogle Scholar
  5. Farde L, Halldin C, Stone-Elander S, Sedvall G (1987) PET analysis of human dopamine receptor subtypes using 11C-SCH 23390 and 11C-raclopride. Psychopharmacology 92:278–284PubMedCrossRefGoogle Scholar
  6. Farde L, Wiesel F-A, Halldin C, Sedvall G (1988) Central D2-dopamine receptor occupancy in schizophrenic patiens treted with antipsychotic drugs. Arch Gen Psychiatry 45:71–76PubMedGoogle Scholar
  7. Farde L, Wiesel FA, Stone-Elander S, Halldin C, Nordstöm AL, Hall H, Sedvall G (1990) D2-dopamine receptors in neuroleptic-naive schizophrenic patients. Arch Gen Psychiatry 47:213–219PubMedGoogle Scholar
  8. Korf J, Sebens JB (1987) Relationship between dopamine receptor occupation by spiperone and acetylcholine: levels in the rat striatum after long-term haloperidol treatment depend upon dopamine innervation. J Neurochem 48:516–521PubMedCrossRefGoogle Scholar
  9. Korf J, Sebens JB, Flentge F, VanderWerf JF (1985) Occupation of dopamine receptors with N-n-propylnorapomorphine or spiperone and acetylcholine levels. J Neurochem 44:314–318PubMedCrossRefGoogle Scholar
  10. Kornhuber J, Riederer P, Reynolds GP, Beckman H, Jellinger K, Gabriel E (1989) 3H-spipeone binding sites in post-mortem brains from schizophrenic patients: relationship to neuroleptic treatment, abnormal movements, and positive symptoms. J Neural Transm 75:1–10PubMedCrossRefGoogle Scholar
  11. Loopuijt LD (1989) Distribution of dopamine D-2 receptors in the rat striatal complex and its comparison with acetylcholinesterase. Brain Res Bull 22:805–817PubMedCrossRefGoogle Scholar
  12. Loopuijt LD, Sebens JB, Korf J (1988) Regional differences in reappearance of D2-dopamine receptors in the rat caudate-putamen complex after irrevesible inactivation. Brain Res 456:263–270PubMedCrossRefGoogle Scholar
  13. Martinot JL, Peron-Magnan P, Huret JD, Mazoyer B, Baron JC, Boulenger JP, Loc’h C, Maziere B, Caillard V, Loo H, Syrota A (1990) Striatal D2 dopaminergic receptors assessed with positron emission tomography and 76Br-bromospiperone in untreated schizophrenic patients. Am J Psychiatry 147:44–50PubMedGoogle Scholar
  14. Meller E, Bohmaker K, Golstein M, Friedhoff AJ (1985) Inactivation of Dl and D2 recptors by N-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline in vivo. J Pharmacol Exp Ther 233:656–662PubMedGoogle Scholar
  15. Sedvall G, Farde L, Persson A, Wiesel FA (1986) Imaging of neurotransmitter receptors in the living human brain. Arch Gen Psychiatry 43:995–1005PubMedGoogle Scholar
  16. Seeman P (1987) The absolute density of neurotransmitter receptors in the brain: example for dopamine receptors. J Pharmacol Methods 17:347–360PubMedCrossRefGoogle Scholar
  17. Seeman P, Ulpian C, Bergeron C, Riederer P, Jellinger K, Gabriel E, Reynolds GP, Tourtelotte WW (1984) Bimodal distribution of dopamine densities in brains of schizophrenics. Science 225:728–731PubMedCrossRefGoogle Scholar
  18. Seeman P, Bzowej N, Guan HC, Bergeron C, Reynolds GP, Bird ED, Riederer P, Jellinger K, Tourtellotte WW (1987) Human brain Dl and D2 dopamine receptors in schizophrenia, Alzheimer’s, Parkinson’s and Huntington’s diseases. Neuropsychopharmacology 1:5–15PubMedCrossRefGoogle Scholar
  19. Sokoloff P, Giros B, Martres M-P, Bouthenet M-L, Schwartz J-C (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146–151PubMedCrossRefGoogle Scholar
  20. Swart JAA, Korf J (1989) Quantification of dopamine D2-receptors by irreversible tracer binding in the living human brain: the model-dependent correction of metabolites. J Cereb Blood Flow Metab 9:906–908PubMedCrossRefGoogle Scholar
  21. Swart JAA, Van der Werf JF, Wiegman T, Paans AM, Vaalburg W, Korf J (1990) In vivo binding of spiperone and N-methylspiperone to dopaminergic and serotonergic sites in the rat brain: multiple modelling and implications for PET scanning. J Cereb Blood Flow Metab 10:297–306PubMedCrossRefGoogle Scholar
  22. Van der Weide J (1988) Determination of the pharmacological profile of the dopamine agonist N-0437. Thesis, University of Groningen, pp 1–142Google Scholar
  23. Van der Werf JF, Sebens JB, Vaalburg W, Korf J (1983) In vivo binding of N-n-propylnorapomorphine in the rat brain: regional localization, quantification in striatum and lack of correlation with dopamine metabolism. Eur J Pharmacol 87:259–270PubMedCrossRefGoogle Scholar
  24. Van der Werf JF, Sebens JB, Korf J (1984a) In vivo binding of N-n-propylnorapo-morphine in the rat striatum: quantification after lesions produced by kainate, 6-hydroxydopamine and decortication. Eur J Pharmacol 102:251–259PubMedCrossRefGoogle Scholar
  25. Van der Werf JF, Van het Schip F, Sebens JB, Korf J (1984b) Quantification of in vivo spiperone binding in the rat striatum after lesions produced by kainate or decortication. Eur J Pharmacol 102:387–399PubMedCrossRefGoogle Scholar
  26. Wolkin A, Barouche F, Wolf AP, Rotrosen J, Fowler JS, Shiue C-Y, Cooper TB, Brodie JD (1989) Dopamine blockade and clinical response: evidence for two biological subgroups of schizophrenia. Am J Psychiatry 46:905–908Google Scholar
  27. Wong DF, Wagner HN, Larry ET, Dannals RF, Pearlson GD, Links GM, Tamminga CA, Bronssolle EP, Ravert HT, Wilson AA, Toang JKT, Malot J, Williams JA, O’Tuama LA, Snyder SH, Kuhar MJ, Gjedde A (1986) Positron emission tomography reveals elevated D2 dopamine receptors in drug naive schizophrenics. Science 234:1558–1563PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • J. Korf
    • 1
  • S. Zijlstra
  • J. A. A. Swart
  • J. W. Louwerens
  1. 1.Department of Biological PsychiatryPsychiatric University ClinicEZ GroningenThe Netherlands

Personalised recommendations