Neuroreceptor Imaging Studies and the Mechanism of Action of Antipsychotic Drugs

  • Valeria Bigliani
  • Lyn S. Pilowsky
  • Geraldo Busatto


Neuroimaging techniques have brought fundamental contributions to the neurosciences, allowing the study of the living human brain and the effects of the drugs in it. This is specially relevant in psychiatry, as psychosis particularly affects higher human functions such as language and emotions. PET and SPET studies not only confirmed in vitro studies correlating dopamine with antipsychotic action, but also have extended knowledge in the field. These techniques were able to link specific dopamine receptors with their localization in the brain, their affinity, and the relation with clinical effects: side effects. They also made it possible to investigate the involvement of other neurotransmitter systems, such as the serotonergic, in the mechanism of action of antipsychotic drugs. PET and SPET neuroimaging is becoming a requirement at all stages of new drug development. The study of the mechanism of action of the existent antipsychotic drugs with neuroimaging techniques is vital for the process of designing better and less toxic drugs for this devastating illness.


Positron Emission Tomography Antipsychotic Drug Receptor Occupancy Single Photon Emission Tomography Atypical Antipsychotic Drug 
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.


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  1. Aghajanian GK, Marek GJ (2000) Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Rev 31:302–312PubMedCrossRefGoogle Scholar
  2. Akbarian S, Vinuela A, Kim JJ, Potkin SG, Bunney WE Jr, Jones EG (1993) Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development. Arch Gen Psychiatry 50:178–187PubMedCrossRefGoogle Scholar
  3. Arranz MJ, Munro J, Sham P et al (1998) Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response. Schizophr Res 32:93–99PubMedCrossRefGoogle Scholar
  4. Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152PubMedCrossRefGoogle Scholar
  5. Bigliani V, Mulligan RS, Acton PD, Visvikis D, Ell PJ, Stephenson C, Kerwin RW, Pilowsky LS (1999) In vivo occupancy of striatal and temporal cortical D2/D3 dopamine receptors by typical antipsychotic drugs — a [123I] epidepride single photon emission tomography (SPET) study. Br J Psychiatry 175:231–238PubMedCrossRefGoogle Scholar
  6. Bigliani V, Mulligan RS, Acton PD, Ohlsen RI, Pike VW, Ell PJ, Gacinovic S, Kerwin RW, Pilowsky LS (2000) Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine — a 123I epidepride single photon emission tomography (SPET) study. Psychopharmacology 150:132–140PubMedCrossRefGoogle Scholar
  7. Bilder RM, Goldman RS, Volavka J et al (2002) Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 159:1018–1028PubMedCrossRefGoogle Scholar
  8. Bressan RA, Pilowsky LS (2000) Imaging the glutamatergic system in vivo — relevance to schizophrenia. Eur J Nucl Med 27:1723–1731PubMedCrossRefGoogle Scholar
  9. Bressan RA, Erlandsson K, Jones HM, Mulligan R, Flanagan RJ, Ell PJ, Pilowsky LS (2003a) Is regionally selective D(2)/D(3) dopamine occupancy sufficient for atypical antipsychotic effect? An in vivo quantitative [(123)I]epidepride SPET study of amisulpride-treated patients. Am J Psychiatry 160:1413–1420PubMedCrossRefGoogle Scholar
  10. Bressan RA, Erlandsson K, Jones HM, Mulligan RS, Ell PJ, Pilowsky LS (2003b) Optimizing limbic selective D2/D3 receptor occupancy by risperidone: a [123I]-epidepride SPET study. J Clin Psychopharmacol 23:5–14PubMedCrossRefGoogle Scholar
  11. Brucke T, Roth J, Podrecka I, Strobi R, Wenger S, Asenbaum S (1992) Striatal dopamine D2 blockade by typical and atypical neuroleptics. Lancet 339:497PubMedCrossRefGoogle Scholar
  12. Buckland PR, O’Donovan MC, McGuffin P (1993) Clozapine and sulpiride up-regulate dopamine D3 receptor mRNA levels. Neuropharmacology 32:901–907PubMedCrossRefGoogle Scholar
  13. Burris KD, Molski TF, Xu C et al (2002) Aripiprazole, a novel antipsychotic, is a high affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302:381–389PubMedCrossRefGoogle Scholar
  14. Busatto GF, Kerwin RW (1997) Perspectives on the role of serotonergic mechanisms in the pharmacology of schizophrenia. J Psychopharmacol 11:3–12CrossRefGoogle Scholar
  15. Busatto GF, Pilowsky LS, Costa DC, Ell PJ, Verhoeff NPLG, Kerwin RW (1995) Dopamine D2 receptor blockade in vivo with the novel antipsychotics risperidone and remoxipride — an 123I IBZM single photon emission tomography (SPET) study. Psychopharmacology 117:55–61PubMedCrossRefGoogle Scholar
  16. Carlsson A, Lindqvist M (1963) Effect of chlorpromazine and haloperidol on formation of 3-mehtoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 20:140–144CrossRefGoogle Scholar
  17. Chiodo LA, Bunney BS (1983) Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopamine neurons. J Neurosci 3: 1607–1619PubMedGoogle Scholar
  18. Chiodo LA, Bunney BS (1985) Possible mechanisms by which repeated clozapine administration differentially affects the activity of two subpopulations of midbrain dopamine neurons. J Neurosci 5:2539–2544PubMedGoogle Scholar
  19. Chou YH, Halldin C, Farde L (2003) Occupancy of 5-HT1A receptors by clozapine in the primate brain: a PET study. Psychopharmacology (Berl) 166:234–240Google Scholar
  20. Chua SE, McKenna PJ (1995) Schizophrenia: a brain disease? A critical review of structural and functional cerebral abnormality in the disorder. Br J Psychiatry 166:563–582PubMedCrossRefGoogle Scholar
  21. Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–483PubMedCrossRefGoogle Scholar
  22. Crow TJ (1980) Molecular pathology of schizophrenia: more than one disease process? BMJ 280: 66–68PubMedCrossRefGoogle Scholar
  23. Deniker P (1990) The neuroleptics: a historical survey. Acta Psychiatr Scand 82[Suppl 358]:83–87CrossRefGoogle Scholar
  24. Deutch AY, Moghaddan B, Innis RB, Krystal JH, Aghajanian GK, Bunney BS, Charney DS (1991) Mechanisms of action of atypical antipsychotic drugs. Implication for novel therapeutic strategies for schizophrenia. Schizophr Res 4:121–156Google Scholar
  25. Dresel S, Mager T, Rossmuller B, Meisenzahl E, Hahn K, Moller HJ, Tatsch K (1999) In vivo effects of olanzapine on striatal dopamine D(2)/D(3) receptor binding in schizophrenic patients: an iodine-123 iodobenzamide single-photon emission tomography study. Eur J Nucl Med 26:862–868PubMedCrossRefGoogle Scholar
  26. Erlandsson K, Bressan RA, Mulligan RS, Gunn RN, Cunningham VJ, Owens J, Wyper D, Ell PJ, Pilowsky LS (2003) Kinetic modelling of [123I]CNS 1261 — a potential SPET tracer for the NMDA receptor. Nucl Med Biol 30:441–454PubMedCrossRefGoogle Scholar
  27. Farde L, Hall H, Ehrin E, Sedvall G (1986) Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science 231:258–261PubMedCrossRefGoogle Scholar
  28. Farde L, Wiesel A, Nordstrom AL, Sedvall G (1989) D1-and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology 99: S28–S31PubMedCrossRefGoogle Scholar
  29. Farde L, Nordstrom AL, Wiesel A, Pauli S, Halldin C, Sedvall G (1992) Positron emission tomography analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side-effects. Arch Gen Psychiatry 49:538–543PubMedCrossRefGoogle Scholar
  30. Farde L, Nordstrom AL, Nyberg, Halldin C, Sedvall G (1994) D1-, D2-and 5HT2-receptor occupancy in clozapine-treated patients. J Clin Psychiatry 55[Suppl B]:67–69PubMedGoogle Scholar
  31. Farde L, Suhara T, Nyberg S, Karlsson P, Nakashima Y, Hietala J, Halldin C (1997) A PET study of 11C FLB-457 binding to extrastriatal D2 dopamine receptors in healthy subjects and antipsychotic drug-treated patients. Psychopharmacology 133:396–404CrossRefGoogle Scholar
  32. Fulton B, Goa KL (1997) Olanzapine. A review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychoses. Ref Drugs 53:281–298CrossRefGoogle Scholar
  33. Gruzelier J, Seymour K, Wilson L, Jolley A, Hirsch S (1998) Impairments on neuropsychologic tests of temporohippocampal and frontohippocampal functions and word fluency in remitting schizophrenia and affective disorders. Arch Gen Psychiatry 45:623–629CrossRefGoogle Scholar
  34. Hietala J, Syvälahti E, Vilkman H, Vuorio K, Räkköläinen V, Bergman J, Haaparanta M, Solin O, Kuoppamäki M, Eronen E, Ruotsalainen U, Salokangas RKR (1998) Depressive symptoms and presynaptic dopaminergic function in neuroleptic-naïve schizophrenia. Schizophr Res 35:41–50CrossRefGoogle Scholar
  35. Jackson DM, Ryan C, Eveden J, Mohell N (1994) Preclinical findings with new antipsychotic agents: what makes them atypical? Acta Psychiatr Scand 89[Suppl 380]:41–48CrossRefGoogle Scholar
  36. Johnstone EC, Crow TJ, Frith CD, Carney MWP, Price JS (1978) Mechanism of the antipsychotic effect in the treatment of acute schizophrenia. Lancet 22:848–851CrossRefGoogle Scholar
  37. Jones H, Travis MJ, Mulligan RS et al (2001) In vivo 5HT2a receptor blockade by quetiapine. An R91150 single photon emission tomography study. Psychopharmacology (Berl) 157:60–66CrossRefGoogle Scholar
  38. Joyce JN, Goldsmith SG, Gurevich EV (1997) Limbic circuits and monoamine receptors: dissecting the effects of antipsychotics from disease processes. J Psychiatr Res 31:197–217CrossRefGoogle Scholar
  39. Kane J, Honigfeld G, Singer J et al (1988) Clozapine for the treatment resistant schizophrenic. Arch Gen Psychiatry 45:789–796PubMedCrossRefGoogle Scholar
  40. Kapur S, Remington G, Jones C, Wilson A, da Suva J, Houle S, Zipursky R (1996) High levels of dopamine D2 receptor occupancy with low dose haloperidol treatment: a PET study. Am J Psychiatry 153:948–950PubMedGoogle Scholar
  41. Kapur S, Zipursky R, Jones C, Remington G, Houle S (2000a) Relationship between dopamine D2 occupancy, clinical response and side-effects: a double blind PET study of first episode schizophrenia. Am J Psychiatry 157:514–520PubMedCrossRefGoogle Scholar
  42. Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P (2000b) A positron emission tomography study of quetiapine in schizophrenia. Arch Gen Psychiatry 57:553–559PubMedCrossRefGoogle Scholar
  43. Kerwin RW (1994) The new atypical antipsychotics. Br J Psychiatry 164:141–148PubMedCrossRefGoogle Scholar
  44. Kerwin R, Pilowsky L (1994) The management of patients with schizophrenia. In: Murray PC, Ell PJ (eds) Nuclear medicine in clinical diagnosis and treatment, vol 1. Churchill Livingstone, Edinburgh, pp 607–611Google Scholar
  45. Kessler RM, Meltzer HY (2002) Regional selectivity in clozapine treatment? Am J Psychiatry 159: 1064–1065PubMedCrossRefGoogle Scholar
  46. Knable MB, Heinz A, Raedler T, Weinberger DR (1997) Extrapyramidal side effects with risperidone and haloperidol at comparable D2 receptor occupancy levels. Psychiatry Res 75:91–101CrossRefGoogle Scholar
  47. Kolakowska T, Williams AO, Ardern M, Reveley MA, Jambor K, Gelder MG, Mandelbrote BM (1985) Schizophrenia with good and poor outcome I: early clinical features, response to neuroleptics and signs of organic dysfunction. Br J Psychiatry 146:229–246PubMedCrossRefGoogle Scholar
  48. Lane HY, Chang YC, Chiu CC et al (2002) Association of risperidone treatment response with a polymorphism in the 5-HT2A receptor gene. Am J Psychiatry 159:1593–1595PubMedCrossRefGoogle Scholar
  49. Laruelle M, Abi-Dargham A, Van Dick H et al (1996) Single photon emission computerised tomography imaging induced dopamine release in drug free schizophrenic patients. Proc Natl Acad Sci U S A 93:9235–9240PubMedCrossRefGoogle Scholar
  50. Leucht S, Barnes TR, Kissling W, Engel RR, Correll C, Kane JM (2003) Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry 160:1209–1222PubMedCrossRefGoogle Scholar
  51. Levant B (1997) The D3 dopamine receptor: neurobiology and potential clinical relevance. Pharmacol Rev Am Soc Pharmacol Exp Ther 49:231–252Google Scholar
  52. Lidow MS, Goldman-Rakic PS (1994) A common action of clozapine, haloperidol and remox-ipride on D1-and D2-dopaminergic receptors in the primate cerebral cortex. Proc Natl Acad SciUS A 91:4353–4356CrossRefGoogle Scholar
  53. Lidow MS, Williams GV, Goldman-Rakic PS (1998) The cerebral cortex: a case for a common site of action of antipsychotics. Trends Pharmacol Sci 19:136–140PubMedCrossRefGoogle Scholar
  54. Lidsky TI (1995) Reevaluation of the mesolimbic hypothesis of antipsychotic drug action. Schizophr Bull 21:67–74PubMedCrossRefGoogle Scholar
  55. Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacol-ogy 21[Suppl 1]:106S–115SGoogle Scholar
  56. Meltzer HY, Matsubara S, Lee JC (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 251: 238–246PubMedGoogle Scholar
  57. Moore H, West AR, Grace AA (1999) The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia. Biol Psychiatry 46:40–55PubMedCrossRefGoogle Scholar
  58. Nolte J (1999) Drives, emotion and memories: the hypothalamus and the limbic system. In: Nolte J (ed) The human brain — an introduction to its functional anatomy, 4th edn. Mosby, New York, pp 537–563Google Scholar
  59. Nordstrom AL, Farde L, Wiesel A, Forslund K, Pauli S, Halldin C, Uppfeldt G (1993) Central D2 dopamine receptor occupancy in relation to antipsychotic drug effect: a double blind PET study of schizophrenic patients. Biol Psychiatry 33:227–235PubMedCrossRefGoogle Scholar
  60. Nordstrom AL, Farde L, Nyberg S, Karlsson P et al (1995) D1, D2, 5HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry 152:1444–1449PubMedGoogle Scholar
  61. Nyberg S, Nakashima Y, Nordstrom AL et al (1996) Positron emission tomography of in-vivo binding characteristics of atypical antipsychotic drugs. Review of D2 and 5-HT2 receptor occupancy studies and clinical response. Br J Psychiatry [Suppl] 29:40–44Google Scholar
  62. Owens DC (1998) The drug treatment of schizophrenia. In: Stein G, Wilkinson G (eds) Seminars in general adult psychiatry, vol 1. Royal College of Psychiatrists, London, pp 381–453Google Scholar
  63. Peroutka SJ, Snyder SH (1980) Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha-adrenergic and histaminergic receptors to clinical potency. Am J Psychiatry 137: 1518–1522PubMedGoogle Scholar
  64. Pickar D (1995) Prospects for pharmacotherapy of schizophrenia. Lancet 345:557–562PubMedCrossRefGoogle Scholar
  65. Pilowsky LS, Costa DC, Ell PJ, Murray R, Verhoeff N, Kerwin RW (1992) Clozapine, single photon emission tomography and the D2 dopamine receptor blockade hypothesis of schizophrenia. Lancet 340:199–202PubMedCrossRefGoogle Scholar
  66. Pilowsky LS, Costa DC, Ell PJ, Murray R, Verhoeff N, Kerwin RW (1993) Antipsychotic medication, D2 dopamine receptor blockade and clinical response — a 1231IBZM SPET (single photon emission tomography) study. Psychol Med 23:791–799PubMedCrossRefGoogle Scholar
  67. Pilowsky LS, Busatto GF, Taylor M, Costa DC, Sharma T, Sigmundsson T, Ell PJ, Nohria V, Kerwin RW (1996) Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine — a 123I IBZM single photon emission tomography (SPET) study. Psychopharmacology 124:148–153PubMedCrossRefGoogle Scholar
  68. Pilowsky LS, Mulligan R, Acton P, Costa D, Ell P, Kerwin RW (1997) Limbic selectivity of clozapine. Lancet 350:490–491CrossRefGoogle Scholar
  69. Rosenbloom M (2002) Chlorpromazine and the psychopharmacologic revolution. JAMA 287: 1860–1861PubMedCrossRefGoogle Scholar
  70. Roth BL, Meltzer HY, Khan N (1998) Binding of typical and atypical antipsychotic drugs to multiple neurotransmitter receptors. Adv Pharmacol 42:482–485PubMedCrossRefGoogle Scholar
  71. Seeman P, Tallerico T (1998) Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry 3:123–134PubMedCrossRefGoogle Scholar
  72. Seeman P, Tallerico T (1999) Rapid release of antipsychotic drugs from dopamine D2 receptors: an explanation for low receptor occupancy and early clinical relapse upon withdrawal of clozapine and quetiapine. Am J Psychiatry 156:876–884PubMedGoogle Scholar
  73. Seeman P, Lee T, Chou-Wong M, Wong K (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261:717–718PubMedCrossRefGoogle Scholar
  74. Sirota P, Epstein B, Benatov R et al (2001) An open study of buspirone augmentation of neuroleptics in patients with schizophrenia. J Clin Psychopharmacol 21:454–455PubMedCrossRefGoogle Scholar
  75. Stephenson CM, Bigliani V, Jones HM, Kerwin RW, Pilowsky LS, Mulligan RS, Visvikis D, Ell PJ, Acton PD (2000) Striatal and extra-striatal D2/D3 dopamine receptor occupancy by quetiapine in vivo: 123I-epidepride single photon emission tomography (SPET) study. Br J Psychiatry 177:408–415PubMedCrossRefGoogle Scholar
  76. Strange PG (2001) Antipsychotic drugs: importance of dopamine receptors for mechanisms of therapeutic action and side-effects. Pharmacol Rev 53:119–134PubMedGoogle Scholar
  77. Stone JM, Bressan RA, Erlandsson K, Davies G, Ell PJ, Pilowsky LS (2003) Atypical antipsychotic drugs preferentially occupy caudate D2/D3 receptors D a voxel based analysis. Eur J Nucl Med Mol Imaging 30[Suppl 2]:S215Google Scholar
  78. Sumiyoshi T, Matsui M, Nohara S et al (2001) Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment. Am J Psychiatry 158:1722–1725PubMedCrossRefGoogle Scholar
  79. Tollefson G, Beasley CM Jr, Tran P (1997) Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 154:456–465Google Scholar
  80. Tran PV, Dellva MA, Tollefson GD, Beasley CM, Potvin JH, Kiesler GM (1997) Extrapyramidal symptoms and tolerability of olanzapine versus haloperidol in the acute treatment of schizophrenia. J Clin Psychiatry 58:205–211CrossRefGoogle Scholar
  81. Travis MJ, Busatto GF, Pilowsky LS et al (1997) Serotonin: 5-HT2A receptor occupancy in vivo and response to the new antipsychotics olanzapine and sertindole. Br J Psychiatry 171:290–291PubMedCrossRefGoogle Scholar
  82. Travis MJ, Busatto GF, Pilowsky LS et al (1998) 5HT2a receptor blockade in schizophrenic patients treated with risperidone or clozapine, a 123l-5-I-R-91150 single photon emission tomography (SPET) study. Br J Psychiatry 173:236–241PubMedCrossRefGoogle Scholar
  83. Trichard C, Paillere-Martinot ML, Attar-Levy D et al (1998) Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients. Am J Psychiatry 155:505–508PubMedGoogle Scholar
  84. Wagner HN, Burns HD, Dannals RF, Wong DF et al (1983) Imaging dopamine receptors in the human brain by positron tomography. Science 221:1264–1266PubMedCrossRefGoogle Scholar
  85. 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 146:905–908PubMedGoogle Scholar
  86. Xiberas X, Martinot JL, Mallet L, Artiges E, Loc’H C, Maziere B, Paillere-Martinot ML (2002) Extrastriatal and striatal D(2) dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry 181:254–255; discussion 255CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2004

Authors and Affiliations

  • Valeria Bigliani
    • 1
  • Lyn S. Pilowsky
    • 2
  • Geraldo Busatto
    • 1
  1. 1.Institute of Nuclear MedicineSao PauloBrazil
  2. 2.Institute of PsychiatryLondonUK

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