Schizophrenie pp 104-124 | Cite as

Bildliche Darstellung von Neurotransmitterinteraktionen in vivo mittels PET

  • G. S. Smith
  • S. L. Dewey
  • J. D. Brodie
  • E. J. Bartlett
  • Ph. Simkowitz
  • R. Riedel
  • H. Fujita
  • R. Cancro
  • A. P. Wolf
Conference paper

Zusammenfassung

Als Konsequenz der Erkenntnis, daß Verhalten die gemeinsame Endstrecke einer komplexen Abfolge neurochemischer und neurophysiologischer Prozesse ist, konzentrierten sich frühe PET-Studien (PET = Positronenemissionstomographie) auf die Verwendung von Tracern des Glukosestoffwechsels und der Durchblutung, die jene Prozesse gleichsam als biochemisches Endergebnis widerspiegeln. In der Erforschung psychotischer Erkrankungen führte diese Schwerpunktsetzung zu Querschnittvergleichen zwischen psychiatrischen Populationen und Kontrollgruppen unter Stimulationsbedingungen einerseits (z. B. Gur et al. 1987) oder therapeutischer Intervention andererseits (z. B. Wolkin et al. 1985). Zwar ließen sich schizophrene Patienten anscheinend durch solche metabolischen Studien mit bildgebenden Verfahren in ihrer funktionellen Organisation von Gesunden unterscheiden (Volkow 1986; Buchsbaum 1982), doch lieferte erst die Entwicklung positronenmarkierter Rezeptorliganden das notwendige Instrumentarium für das Verständnis der Ursachen dieser funktionellen Unterschiede und der neurochemischen Phänomene unter der Therapie.

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Literatur

  1. Arora R, Meltzer H (1991) Serotonin (5HT2) receptor binding in the frontal cortex of schizophrenic patients. J Neural Transmission 85: 19–29CrossRefGoogle Scholar
  2. Bartiett EJ, Brodie JD, Simkowitz P, Dewey S, Rusinek H, Wolf AP, Fowler JS, Volkow ND, Smith G, Wolin A, Cancro R (1994) Effects of haloperidol challenge on regional cerebral glucose utilization in normal human subjects. Am J Psychiatry (in press)Google Scholar
  3. Benes F, Vincent S, Alsterberg G, Bird E, SanGiovanni J (1992) Increased GABAa receptor binding in superficial layers of cingulate cortex in schizophrenics. J Neurosci 12: 924–929PubMedGoogle Scholar
  4. Bouthenet, Souil E, Martres M, Sokoloff P, Giros B, Schwartz J-C (1991) Localization of dopamine D3 receptor RNA in the rat brain using in situ hybridization histochemistry. Brain Res 564: 203–219PubMedCrossRefGoogle Scholar
  5. Bloom F, Costa E, Salmoiraghi G (1965) Anaesthesia and the responsiveness of individual neurons of the caudate nucleus of the cat to acetylcholine, norepinephrine and dopamine administered by microelectrodes. J Pharmacol Exp Ther 50: 244–252Google Scholar
  6. Bonner T (1989) The molecular basis of muscarinic receptor diversity. Trends in Pharmacologic Science 12: 148–151Google Scholar
  7. Bonner T, Young A, Brann M, Buckley N (1988) Cloning and expression of the human and rat m 5 muscarinic acetylcholine receptor gene. Neuron 1: 403–410PubMedCrossRefGoogle Scholar
  8. Bowery N, Hudson A, Price G (1987) GABAa and GABAb receptor site distribution in the rat central nervous system. Neuroscience 20: 365–383PubMedCrossRefGoogle Scholar
  9. Buchsbaum MS, Ingvar DH, Kessler et al. (1982) Cerebral glucography with positron tomography. Arch Gen Psychiatry 41: 1159–1168Google Scholar
  10. Buckley N, Bonner T, Brann M (1989) Localization of a family of muscarinic receptor mRNAs in rat brain. J Neurosci 8: 4646–4662Google Scholar
  11. Bunzow J, Van Tol H, Grandy J et al. (1988) Cloning and expression of a rat D2 dopamine receptor cDNA. Nature:783–787Google Scholar
  12. Bunney B, Agahajanian G (1976) Dopaminergic influence in the basal ganglia: evidence for nigro-striatal feedback regulation. In: Yahr M (ed) The basal ganglia. Raven Press, New York, pp 249–267Google Scholar
  13. Camps M, Cortes R, Gueye B, Probst A, Palacios J (1989) Dopamine receptors in human brain: autoradiographic distribution of D2 sites. Neuroscience 28: 275–290PubMedCrossRefGoogle Scholar
  14. Connor C (1970) Caudate nucleus neurons: correlation of the effects of substantia nigra stimulation with iontophoretic dopamine. J Physiol 208: 691PubMedGoogle Scholar
  15. Coppens H, Slooff C, Paans A, Wiegman T, Vaalberg W, Korf J (1991) High central D2-dopamine receptor occupancy as assessed with positron emission tomography in medicated but therapy resistent schizophrenic patients. Biol Psychiatry 29: 629–634PubMedCrossRefGoogle Scholar
  16. Cortes R, Probst A, Palacios J (1984) Quantitative light microscopic autoradiographic localization of cholinergic muscarinic receptors in human brain: brainstem. Neuroscience 12: 1003–1026PubMedCrossRefGoogle Scholar
  17. Cortes R, Gueye B, Pazos A, Probst A, Palacios J (1989) Dopamine receptors in human brain: autoradiographic distribution of D1 sites. Neuroscience 28: 263–273PubMedCrossRefGoogle Scholar
  18. Cortes R, Probst A, Palacios J (1987) Quantitative light microscopic autoradiographic localization of cholinergic muscarinic receptors in human brain: forebrain. Neuroscience 20: 65–107PubMedCrossRefGoogle Scholar
  19. Cosi C, Wood P (1988) Lack of GABAergic modulation of acetylcholine turnover in the rat thalamus. Neuroscience Letts 87: 293–296CrossRefGoogle Scholar
  20. Dahlstroni A, Fuxe D (1984) Evidence for the existence of monoamine containing neurons in the central nervous system. Acta Physiol Scand 232:155Google Scholar
  21. Deutsch A, Moghaddam B, Innis R et al. (1991) Mechanisms of action of atypical antipsychotic drugs. Schizophr Res 4: 121–156CrossRefGoogle Scholar
  22. Dewey SL, Wolf A, Fowler J (1988) The effects of central cholinergic blockade on 18F-N-methyispiroperidol binding in the human brain. XVI C.I.N.P. Congress 96: 162Google Scholar
  23. Dewey SL, Brodie J, Fowler et al. (1990a) Positron emission Tomography ( PET) studies of the dopaminergic/cholinergic interactions in the baboon brain. Synapse 6: 321–327PubMedCrossRefGoogle Scholar
  24. Dewey SL, Macgregor R, Brodie et al. (1990b) Mapping muscarinic receptors in the human and baboon brain using N-11C-methyl-benztropine. Synapse 5: 213–233PubMedCrossRefGoogle Scholar
  25. Dewey SL, Volkow N, Logan J, MacGregor, Fowler J, Schleyer D, Bendriem B (1990c) Age related decreases in muscarinic cholinergic receptor binding in the human brain measured with positron emission tomography ( PET ). J Neurosci Res 27: 569–575PubMedCrossRefGoogle Scholar
  26. Dewey SL, Logan J, Wolf A et al. (1991) Amphetamine induced decreases in 18F-N-methylspiroperidol binding in the baboon brain using positron emission tomography ( PET ). Synapse 7: 324–327PubMedCrossRefGoogle Scholar
  27. Dewey S, Brodie J, Smith G et al. (1992a) GABAergic modulation of endogenous dopamine and acetylcholine release measured in vivo with positron emission tomography. J Nucl Med 33 /5: 847Google Scholar
  28. Dewey S, Smith G, Logan J et al. (1992b) GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography. J Neurosci 12: 3773–3780PubMedGoogle Scholar
  29. Dewey SL, Smith GS, Logan J, Brodie JD, Fowler JS, Wolf AP (1993a) Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels. Synapse 13: 350–356PubMedCrossRefGoogle Scholar
  30. Dewey SL, Smith GS, Logan J, Brodie JD (1993b) Modulation of central cholinergic activity by GABA and serotonin: PET studies with 11C-benztropine in primates. Neuropsychopharmacology 8: 371–376PubMedGoogle Scholar
  31. Dewey SL, Smith G, Logan J (1993c) Effects of central cholinergic blockade on striatal dopamine release measured with positron emission tomography (PET) in normal human subjects. Proc Natl Acad Sci (USA) (in press)Google Scholar
  32. Farde L, Wiesel F-A, Halldin C et al. (1988) Central D2 receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45: 71–76PubMedGoogle Scholar
  33. Farde L, Wiesel F-A, Stone-Elander S et al. (1990) D2 dopamine receptors in neuroleptic naive schizophrenic patients. Arch Gen Psychiatry 47: 213–219PubMedGoogle Scholar
  34. Ferkany J, Enna S (1980) Interaction between GABA agonists and the cholinergic muscarinic system in rat corpus striatum. Life Sci 27: 143–149PubMedCrossRefGoogle Scholar
  35. Fibiger H, Miller J (1977) An anatomical and electrophysiologic investigation of the serotonergic projection from the dorsal raphe nucleus to the substantia nigra in the rat. Neuroscience 2: 975–987CrossRefGoogle Scholar
  36. Flicker C, Ferris S, Serby M (1990) Scopolamine effects on memory, language, visuospatial praxis and psychomotor speed. Psychopharmacology 100: 243PubMedCrossRefGoogle Scholar
  37. Fleischacker W, Barnas C, Stuppack C, Unterweger C, Hinterhuber H (1987) Zotepine in the treatment of negative symptoms in chronic schizophrenia. Pharmacopsychiatry 20: 58–60CrossRefGoogle Scholar
  38. Freed WJ (1988) The therapeutic latency of neuroleptic drugs and nonspecific postjunctional supersensitivity. Schizophr Bull 14: 269–777PubMedGoogle Scholar
  39. Fremeau R, Duncan G, Fornaretto M et al. (1991) Localization of D1 receptor mRNA in brain supports a role in cognitive, affective and neuroendocrine aspects of dopaminergic transmission. Proc Natl Acad Sci (USA) 88: 3772–3776CrossRefGoogle Scholar
  40. Friedhoff AJ (1986) A dopamine dependent restitutive system for the maintenance of mental normalcy. Ann N Y Acad Sci 463: 47–52PubMedCrossRefGoogle Scholar
  41. Gale K, Casu M (1980) Dynamic utilization of GABA in substantia nigra: regulation by dopamine and GABA in the striatum and its clinical and behavioral implications. Mol Cell Biochem 39: 369–405CrossRefGoogle Scholar
  42. Goldberger T, Weinberger D, Pliskin N (1989) Schizophr Res 2: 251–257CrossRefGoogle Scholar
  43. Gur R, Resnick S, Gur R, Alavi A, Caroff S, Kushner M, Reivich M (1987) Regional brain function in schizophrenia. Arch Gen Psychiatry 44: 119–125PubMedGoogle Scholar
  44. Honer W, Prohovnik I, Smith G, Lucas L (1988) Scopolamine reduces frontal cortex perfusion. J Cereb Blood Flow Metab 8: 635–641PubMedCrossRefGoogle Scholar
  45. Hoyer D, Pazos A, Probst A, Palaclos J (1986) Serotonin receptors in the human brain II. characterization and autoradiographic localization of 5-HT1C and 5-HT2 recognition sites. Brain Res 376: 97–107PubMedCrossRefGoogle Scholar
  46. Innis R, Mallison R, Al-Tikriti M et al. (1992) Amphetamine stimulated dopamine release competes in vivo for 123I-IBZM binding to the D2 receptor in nonhuman primates. Synapse 10: 177–184PubMedCrossRefGoogle Scholar
  47. Jones B, Cuello A (1989) Afferents to the basal forebrain cholinergic cell area from pontomesencephalic, catecholamine, serotonin and acetylcholine neurons. Neuroscience 31: 37–61PubMedCrossRefGoogle Scholar
  48. Kalivas P, Duffy P, Eberhardt H (1990) Modulation of A10 dopamine neurons by GABA agonists. J Pharmacol Exp Ther 253: 858–866PubMedGoogle Scholar
  49. Kubota Y, Inagaki S, Kito S, Wu J (1987) Dopaminergic axons directly make synapses with GABAergic neurons in the rat neostriatum. Brain Research 406: 147–156PubMedCrossRefGoogle Scholar
  50. Kuczenski R, Segal D (1989) Concomitant characterization of behavioral and striatal neurotransmitter response to amphetamine using in vivo microdialysis. J Neurosci 9: 2051–2065PubMedGoogle Scholar
  51. Ladinsky H, Consolo S, Perl G, Crunelli V, Samanin R (1978) Pharmacological evidence for a serotonergic-cholinergic link in the striatum. In: Jenden D (ed) Cholinergic mechanisms and psychopharmacology. Plenum Press, New York, pp 615–628Google Scholar
  52. Leysen J, Niemeegers C, Tollenaere J, Laduron P (1978) Serotonergic component of neuroleptic receptors. Nature 272: 168–171PubMedCrossRefGoogle Scholar
  53. Lindvall O, Bjorklund A (1974) The organization of the ascending catecholamine neuron system in the rat brain. Acta Physiol Scand 412: 1–48Google Scholar
  54. Luabeya M, Maloteaux J-M, Laduron P (1984) Regional and cortical laminar distributions of serotonin, benzodiazepine, muscarinic and dopamine receptor in human brain. J Neurochem 43: 1068–1071PubMedCrossRefGoogle Scholar
  55. McCulloch J, Savaki H, Sokoloff L (1982) Distribution of effects of haloperidol on energy metabolism in the rat brain. Brain Res 243: 81–90PubMedCrossRefGoogle Scholar
  56. McGeer P, McGeer E (1977) Possible changes in striatal and limbic cholinergic system in schizophrenia. Arch Gen Psychiatry 34: 1319–1323PubMedGoogle Scholar
  57. McGeer, P, McGeer, E (1984) Cholinergic systems and cholinergic pathology. In: Laijtha A (ed) Handbook of neurochemistry. Plenum Press, New York, pp 211–288Google Scholar
  58. McGeer P, McGeer E (1989) Amino acid neurotransmitters. In: Siegel G (ed) Basic neurochemistry. Plenum Press, New York, pp 311–332Google Scholar
  59. Matthew R, Wilson W (1991) Substance abuse and cerebral blood flow. Am J Psychiatry 148: 292–305Google Scholar
  60. Mahadik S, Laev H, Korenovsky A, Karpiak S (1988) Haloperidol alters rat CNS cholinergic system. Biol Psychiatry 24: 199–217PubMedCrossRefGoogle Scholar
  61. Mao C, Cheney D, Marco E, Revuelta A, Costa E (1977) Turnover times of GABA and acetylcholine in the nucleus caudatus, nucleus accumbens, globus pallidus and substantia nigra: effects of repeated administration of haloperidol. Brain Res 132: 375–379PubMedCrossRefGoogle Scholar
  62. Meador-Woodruff J, Mansour A, Bunzow J, Van Tol H, Watson S, Civelli O (1989) Distri- bution of D2 dopamine receptor mRNA in rat brain. Proc Natl Acad Sci 86: 7625–7628PubMedCrossRefGoogle Scholar
  63. Meltzer H (1991) The mechanism of action of novel antipsychotic drugs. Schizophr Bull 17: 263–287PubMedGoogle Scholar
  64. Meltzer H (1989) Clinical studies on the mechanism of action of clozapine: the dopamineserotonin hypothesis of schizophrenia. Psychopharmacology 99: 18–27CrossRefGoogle Scholar
  65. Mesulam M, Mufson E, Levey A, Wainer B (1983) Cholinergic innervation of the cortex by the basal forebrain. J Comp Neurol 214: 170–197PubMedCrossRefGoogle Scholar
  66. Miller R (1987) Time course of neuroleptic therapy for psychosis. Psychopharmacology 92: 405–415PubMedCrossRefGoogle Scholar
  67. Nordstrom A-L, Farde L, Halldin C (1992) Time course of D2-dopamine receptor occupancy examined by PET after single oral doses of haloperidol. Psychopharmacology 106: 433–438PubMedCrossRefGoogle Scholar
  68. Palacios J (1990) Distribution of serotonin receptors. Ann NY Acad Sci 600: 36–52PubMedCrossRefGoogle Scholar
  69. Pazos A, Probst A, Palacios J (1987) Serotonin receptors in the human brain-IV autoradio-graphic mapping of serotonin 2 receptors. Neuroscience 21: 123–139PubMedCrossRefGoogle Scholar
  70. Peroutka S (1989) 5-hydroxytryptamine receptor subtypes: molecular, biochemical and physiological characterization. Trends Neurosci 11:496–500CrossRefGoogle Scholar
  71. Peroutka S, Snyder S (1980) Relationship of neuroleptic drug effects at brain dopamine serotonin, adrenergic and histainine to clinical potency. Arch Gen Psychiatry 137: 1518–1522Google Scholar
  72. Perry T, Buchanan J, Kish S, Hansen S (1979) GABA deficiency in the brains of schizophrenic patients. Lancet 1: 237PubMedCrossRefGoogle Scholar
  73. Pickar D (1988) Perspectives on a time-dependent model of neuroleptic action. Schizophr Bull 14: 255–268PubMedGoogle Scholar
  74. Pizzolato G, Soncrant ‘IT, Rapoport SI (1984) Haloperidol and cerebral metabolism in the conscious rat: relation to pharmacokinetics. J Neurochem 43: 724–732PubMedCrossRefGoogle Scholar
  75. Saykin A, Gur R, Gur R, Moziey L, Resnick S, Kester D, Stafiniak P (1991) Neuropsychological function in schizophrenia: selective impairment in memory and learning. Arch Gen Psychiatry 48: 618–624PubMedGoogle Scholar
  76. Smith M, Wolf A, Brodie J et al. (1988) Serial 18F-N-methylspiroperidol PET studies to measure change in antipsychotic D2 drug receptor occupancy in schizophrenic patients. Biol Psychiatry 23: 653–663PubMedCrossRefGoogle Scholar
  77. Smith Y, Bolam J (1990) The output neurons and the dopaminergic neurons of the substantia nigra receive a GABA containing input from the globus pallidus in the rat. J Comp Neurol 296: 47–64PubMedCrossRefGoogle Scholar
  78. Sokoloff P, Giros B, Martres M, Bouthnet M, Schwartz J-C (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347: 146–151PubMedCrossRefGoogle Scholar
  79. Stahl S, Thornton J, Simpson M, Berger P, Napoliello M (1985) Gamma-vinyl-GABA treatment of tardive dyskinesia and other movement disorders. Biol Psychiatry 20: 888–893PubMedCrossRefGoogle Scholar
  80. Stahl S, Wets K (1987) Indoleamine-s and schizophrenia. In: Henn F, deLisi L (eds) Handbook of schizophrenia, vol 2, pp 257–296Google Scholar
  81. Steinbusch H (1981) Distribution of serotonin immunoreactivity in the central nervous system of the rat. Neuroscience 6: 557–618PubMedCrossRefGoogle Scholar
  82. Tamminga C, Thaker G, Hare T, Ferraro T (1983) GABA agonist therapy improves tardive dyskinesia. Lancet 11: 97–98CrossRefGoogle Scholar
  83. Tandon R, Greden J (1989) Cholinergic hyperactivity and negative schizophrenic symptoms. A model of cholinergic/dopaminergic interactions in schizophrenia. Arch Gen Psychiatry 34: 236–239Google Scholar
  84. Thaker G, Tamminga C, Alpha L, Lafferman J, Ferraro T, Hare T (1987) Brain gamma aminobutyric acid abnormality in tardive dyskinesia. Arch Gen Psychiatry 44: 522–529PubMedGoogle Scholar
  85. Van Tol H, Bunzow J, Guan H, Sunahara R, Seeman P, Niznik H, Civelli O (1991) Cloning of the gene for the human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350: 610–614PubMedCrossRefGoogle Scholar
  86. Vilaro M, Wiederhold K, Palacios J, Menaod G (1991) Muscarinic cholinergic receptors in the rat caudate-putamen and olfactory tubercule belong predominantly to the m 4 class. Neuroscience 40: 159–167PubMedCrossRefGoogle Scholar
  87. Volkow ND, Brodie JD, Wolf AP et al. (1986) Brain organization in schizophrenia. J Cereb Blood Flow Metab 6: 441–446PubMedCrossRefGoogle Scholar
  88. Wolkowitz O, Pickar D (1991) Benzodiazepines in the treatment of schizophrenia: a review and reappraisal. Am J Psychiatry 148: 714–726PubMedGoogle Scholar
  89. Wolkin A, Jaeger J, Brodie J et al. (1985) Persistence of cerebral metabolic abnormalities in chronic schizophrenia as determined by positron emission tomography. Am J Psychiatry 145: 251–253Google Scholar
  90. Wolkin A, Brodie J, Barouche F, Rotrosen J, Wolf A, Cooper T (1989a) Dopamine receptor occupancy and haloperidol plasma levels. Arch Gen Psychiatry 46: 482–486PubMedGoogle Scholar
  91. Wolkin A, Barouche F, Wolf A et al. (1989b) Dopamine blockade and clinical response: evidence for two biological subgroups of schizophrenia. Am J Psychiatry 146: 905–908PubMedGoogle Scholar
  92. Wong D, Gjedde A, Wagner H, Dannals R, Douglass K, Links J, Kuhar M (1986) Quantification of neuroreceptors in the living human brain II. Inhibition studies of receptor density and affinity. J Cereb Blood Flow Metab 6: 147–153PubMedCrossRefGoogle Scholar
  93. Wood P, Etienne P, Smarthji L (1982) GABAergic regulation of nigrostriatal neurons: coupling of benzodiazepine and GABA receptors. Prog Neuropsychopharmacol Biol Psychiatry 6: 471–474PubMedCrossRefGoogle Scholar
  94. Zaborszky L (1989) Afferent connections of the forebrain cholinergic projection neurons. In: Frotscher M, Misgeld U (eds) Central cholinergic synaptic transmission. Birkhäuser, Basel, pp 12–32CrossRefGoogle Scholar
  95. Zezula J, Cortes R, Probst A, Palacios J (1988) Benzodiazepine receptor sites in the human brain: autoradiographic mapping. Neuroscience 22: 771–795CrossRefGoogle Scholar
  96. Zhou Q, Grandy D, Thambi L et al. (1990) Cloning and expression of human and rat D1 dopamine receptor. Nature 347: 76–80PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • G. S. Smith
  • S. L. Dewey
  • J. D. Brodie
  • E. J. Bartlett
  • Ph. Simkowitz
  • R. Riedel
  • H. Fujita
  • R. Cancro
  • A. P. Wolf

There are no affiliations available

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