The depolarization block hypothesis of neuroleptic action: implications for the etiology and treatment of schizophrenia

  • A. A. Grace
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 36)


Antipsychotic drugs are known to block dopamine receptors soon after their administration, resulting in an increase in dopamine neuron firing and dopamine turnover. Nonetheless, antipsychotic drugs must be administered repeatedly to schizophrenics before therapeutic benefits are produced. Recordings from dopamine neurons in rats have revealed that chronic antipsychotic drug treatment results in the time-dependent inactivation of dopamine neuron firing via over-excitation, or depolarization block. Furthermore, the clinical profile of the response to antipsychotic drugs appears to correspond to the dopamine system affected: antipsychotic drugs that exert therapeutic actions in schizophrenics inactivate dopamine neuron firing in the limbic-related ventral tegmental area, whereas drugs that precipitate extrapyramidal side effects cause depolarization block of the motor-related substantia nigra dopamine cells.

One factor that remains unresolved with regard to the actions of antipsychotic drugs is the relationship between dopamine turnover and depolarization block — i.e., why does a significant level of dopamine release or turnover remain after antipsychotic drug treatment if dopamine cells are no longer firing? We addressed this question using an acute model of neuroleptic-induced depolarization block. In this model, dopamine cells recorded in rats one month after partial dopamine lesions could be driven into depolarization block by the acute administration of moderate doses of haloperidol. However, similar doses of haloperidol, which were effective at increasing dopamine levels in the striatum of intact rats, failed to change dopamine levels in lesioned rats. This is consistent with a model in which neuroleptic drugs exert their therapeutic effects in schizophrenics by causing depolarization block in DA cells, thereby preventing further activation of dopamine neuron firing in response to external stimuli. Thus, attenuating the responsivity of the dopamine system to stimuli may be more relevant to the therapeutic actions of antipsychotic drugs than receptor blockade or decreases in absolute levels of dopamine, which could presumably be circumvented by homeostatic adaptations in this highly plastic system.


Ventral Tegmental Area Antipsychotic Drug Dopamine Release Dopamine Neuron Neuron Firing 
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. Abercrombie ED, Hollerman JR, Grace AA (1989) In vivo biochemical correlates of acute depolarization inactivation in substantia nigra dopaminergic neurons. Soc Neurosci Abstr 15; 1002Google Scholar
  2. Aghajanian GK, Bunney BS (1974) Dopaminergic and non-dopaminergic neurons of the substantia nigra: differential responses to putative transmitters. In: Boissier JR, Hippius H, Picho P (eds) Proceedings 9th International Congress of the Collegium Internationale Neuropsychopharmacologicum. Excerpta Medica, Amsterdam, pp 444–452Google Scholar
  3. Aghajanian GK, Bunney BS (1977) Dopamine “autoreceptors”: pharmacological characterization by microiontophoretic single cell recording studies. Naunyn Schmiedebergs Arch Pharmacol 297: 1–7PubMedCrossRefGoogle Scholar
  4. Alfredsson G, Wiesel F-A, Tylec A (1988) Relationships between glutamate and monoamine metabolites in cerebrospinal fluid and serum in healthy volunteers. Biol Psychiatry 23: 689–697PubMedCrossRefGoogle Scholar
  5. Allen RM, Young SJ (1978) Phencyclidine-induced psychosis. Am J Psychiatry 135: 1081–1084PubMedGoogle Scholar
  6. Alpert M, Friedhoff AJ, Marcos LR, Diamond F (1978) Paradoxical reactions to L-dopa in schizophrenic patients. Am J Psychiatry 135: 1327–1332Google Scholar
  7. Andén N-E, Grenhoff J, Svensson TH (1988) Does treatment with haloperidol for 3 weeks produce depolarization block in midbrain dopamine neurons of unanesthetized rats? Psychopharmacology 96: 558–560PubMedCrossRefGoogle Scholar
  8. Angrist BM, Shopsin B, Gershon S (1971) The comparative psychotomimetic effects of stereoisomers of amphetamine. Nature (London) 234: 152–153CrossRefGoogle Scholar
  9. Angrist BM, Rotrosen J, Gershon S (1980) Differential effects of amphetamine and neuroleptics on negative vs. positive symptoms in schizophrenia. Psychopharmacology 72: 17–19PubMedCrossRefGoogle Scholar
  10. Baldessarini RJ (1985) Drugs and the treatment of psychiatric disorders. In: Gilman AG, Goodman LS, Rall TW, Murad F (eds) The pharmacological basis of therapeutics, 7th edn. Macmillan, New York, pp 387–445Google Scholar
  11. Baldessarini RJ, Cohen BM, Teicher MH (1988) Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychosis. Arch Gen Psychiatry 45: 79–91PubMedCrossRefGoogle Scholar
  12. Bannon MJ, Bunney EB, Zigun JR, Skirboll LR, Roth RH (1980) Presynaptic dopamine receptors: insensitivity to kainic acid and the development of supersensitivity following chronic haloperidol. Naunyn-Schmiedebergs Arch Pharmacol 312: 161–164PubMedCrossRefGoogle Scholar
  13. Bannon MJ, Michaud RL, Roth RH (1981) Mesocortical dopamine neurons: lack of autoreceptors modulating dopamine synthesis. Mol Pharmacol 19: 270–275PubMedGoogle Scholar
  14. Bannon MJ, Reinhard JF Jr, Bunney EB, Roth RH (1982) Unique response to antipsychotic drugs is due to the absence of terminal autoreceptors in mesocortical dopamine neurons. Nature (London) 296: 444–446CrossRefGoogle Scholar
  15. Barbieto L, Chéramy A, Godeheu G, Desce JM, Glowinski J (1990) Glutamate receptors of the quisqualate-kainate subtype are involved in the presynaptic regulation of the dopamine release in the cat caudate nucleus in vivo. Eur J Neurosci 2: 304–311CrossRefGoogle Scholar
  16. Benes FM, Bird ED (1987) An analysis of the arrangement of neurons in the cingulate cortex of schizophrenic patients. Arch Gen Psychiatry 44: 608–616PubMedCrossRefGoogle Scholar
  17. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington: clinical, morphological and neurochemical correlations. J Neurol Sci 20: 415–455PubMedCrossRefGoogle Scholar
  18. Biggio G, Casu M, Klimek V, Gessa GL (1980) Dopamine synthesis: tolerance to haloperidol and supersensitivity to apomorphine depend on pre-synaptic receptors. In: Cattabeni F, Racagni G, Spano PF, Costa E (eds) Advances in biochemical psychopharmacology, vol 24. Raven Press, New York, pp 18–22Google Scholar
  19. Blaha CD, Lane RF (1987) Chronic treatment with classical and atypical antipsychotic drugs differentially decreases dopamine release in striatum and nucleus accumbens in vivo. Neurosci Lett 78: 199–204PubMedCrossRefGoogle Scholar
  20. Bogerts B (1985) Evidence for structural changes in the limbic system in schizophrenia. In: Shagass C, Josiassen RC, Bridger WH, Weiss KJ, Stoff D, Simpson GM (eds) Biological psychiatry. Elsevier, New York, pp 1015–1020Google Scholar
  21. Bogerts B, Meertz E, Schonfeld-Bausch R (1985) Basal ganglia and limbic system pathology in schizophrenia. A morphometric study of brain volume and shrinkage. Arch Gen Psychiatry 42: 784–791PubMedCrossRefGoogle Scholar
  22. Bowers MB (1973) 5-HIAA and HVA following probenecid in acute psychotic patients treated with phenothiazines. Psychopharmacologia 28: 309–312Google Scholar
  23. Bowers MB, Swigar ME, Jatlow PI Goicoechea N (1984) Plasma catecholamine metabolites and early response to haloperidol. J Clin Psychiatry 45: 248–251PubMedGoogle Scholar
  24. Bowers MB, Swigar ME, Jatlow PI Hoffman RI (1989) Plasma catecholamine metabolites and treatment response at neuroleptic steady state. Biol Psychiatry 25: 734–738PubMedCrossRefGoogle Scholar
  25. Brown WA, Herz LR (1989) Response to neuroleptic drugs as a device for classifying schizophrenia. Schizophr Bull 15: 123–129PubMedGoogle Scholar
  26. Buchsbaum MS, Wu JC, DeLisi LE, Holcomb HH, Hazlett E, Cooper-Langston K, Kessler R (1987) Positron emission tomography studies of basal ganglia and somatosensory cortex neuroleptic drug effects: differences between normal controls and schizophrenic patients. Biol Psychiatry 22: 479–494PubMedCrossRefGoogle Scholar
  27. Bunney BS, Aghajanian GK (1978) Mesolimbic and mesocortical dopaminergic systems: physiology and pharmacology. In: Lipton MA, DiMascio A (eds) Psychopharmacology: a generation of progress. Raven Press, New York, pp 159–169Google Scholar
  28. Bunney BS, Grace AA (1978) Acute and chronic haloperidol treatment: comparison of effects on nigral dopaminergic cell activity. Life Sci 23: 1715–1728PubMedCrossRefGoogle Scholar
  29. Bunney BS, Grace AA (1979) Effects of chronic haloperidol treatment on nigral dopaminergic cell activity. In: Usdin E, Kopin IJ, Barchas J (eds) Catecholamines: basic and clinical frontiers. Pergamon Press, New York, pp 666–668Google Scholar
  30. Bunney BS, Walters JR, Roth RH, Aghajanian GK (1973) Dopaminergic neurons: effect of antipsychotic drugs and amphetamine on single cell activity. J Pharmacol Exp Ther 185: 560–571PubMedGoogle Scholar
  31. Burt DR, Creese I, Snyder SH (1977) Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 196: 326–328PubMedCrossRefGoogle Scholar
  32. Bustos G, Roth RH (1972) Effect of y-hydroxybutyrate on the release of monoamines from the rat striatum. Biochem Pharmacol 21: 2649–2652PubMedCrossRefGoogle Scholar
  33. Carlsson A, Lindqvist M (1963) Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 20: 140–144CrossRefGoogle Scholar
  34. Carlsson A, Lindqvist M, Magnusson T, Waldeck B (1958) On the presence of 3-hydroxytyramine in brain. Science 127: 471PubMedCrossRefGoogle Scholar
  35. Carlsson A, Fuxe K, Hamberger B, Lindqvist M (1966) Biochemical and histochemical studies on the effects of imipramine-like drugs and (+)-amphetamine on central and peripheral catecholamine neurons. Acta Physiol Scand 67: 481–497PubMedCrossRefGoogle Scholar
  36. Charpentier P (1950) 10-(Dialkylaminoalkyl)-phenothiazines. US Patent 2, 519, 886Google Scholar
  37. Chen J, Paredes W, Gardner EL (1991) Chronic treatment with clozapine selectively decreases basal dopamine release in nucleus accumbens but not in caudateputamen as measured by in vivo brain microdialysis: further evidence for depolarization block. Neurosci Lett 122: 127–131PubMedCrossRefGoogle Scholar
  38. Chéramy A, Romo R, Godeheu G, Baruch P, Glowinski J (1986) In vivo presynaptic control of dopamine release in the cat caudate nucleus. II. Facilitatory or inhibitory influence of L-glutamate. Neuroscience 19: 1081–1090PubMedCrossRefGoogle Scholar
  39. Chesselet MF, Chéramy A, Romo R, Desban M, Glowinski J (1983) GABA in the thalamic motor nuclei modulates dopamine release from two dopaminergic nigrostriatal pathways in the cat. Exp Brain Res 51: 275–282PubMedCrossRefGoogle Scholar
  40. Chiodo LA, Bunney BS (1983) Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons. J Neurosci 3: 1607–1619PubMedGoogle Scholar
  41. 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
  42. Church WH, Justice JB, Neill DB (1987) Detecting behaviorally relevant changes in extracellular dopamine with microdialysis. Brain Res 421: 397–399CrossRefGoogle Scholar
  43. Clow DW, Jhamandas K (1989) Characterization of L-glutamate action on the release of endogenous dopamine from the rat caudate-putamen. J Pharmacol Exp Ther 248: 722–728PubMedGoogle Scholar
  44. Connell PH (1958) Amphetamine psychosis. Chapman & Hall, LondonGoogle Scholar
  45. Conrad AJ Abebe T, Austin R, Forsythe S, Scheibel AB (1991) Hippocampal pyramidal cell disarray in schizophrenia as a bilateral phenomenon. Arch Gen Psychiatry 48: 413–417PubMedCrossRefGoogle Scholar
  46. Cook L, Catania AC (1964) Effects of drugs on avoidance and escape behavior. Fed Proc 23: 818–835PubMedGoogle Scholar
  47. Coyle S, Napier TC, Breese GR (1985) Ontogeny of tolerance to haloperidol: behavioral and biochemical measures. Dev Brain Res 23: 27–38CrossRefGoogle Scholar
  48. Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192: 481–483PubMedCrossRefGoogle Scholar
  49. Curtis DR, Phillis JW, Watkins JC (1960) The chemical excitation of spinal neurons by certain acidic amino acids. J Physiol (London) 150: 656–682Google Scholar
  50. Davidson AB, Weidley E (1976) Differential effects of neuroleptic and other psychotropic agents on acquisition of avoidance in rats. Life Sci 18: 1279–1284PubMedCrossRefGoogle Scholar
  51. Davila R, Manero E, Zumarraga MA, Andia I, Schweitzer JW, Friedhoff AJ (1988a) Plasma homovanillic acid as a predictor of response to neuroleptics. Arch Gen Psychiatry 45: 564–567PubMedCrossRefGoogle Scholar
  52. Davila R, Zumarraga M, Friedhoff AJ, Miller JC (1988b) Characteristics of the adaptive aspects of the dopaminergic system. Psychopharmacol Bull 24: 338–340PubMedGoogle Scholar
  53. Deakin JFW, Slater P., Simpson MDC, Gilchrist AC, Skan W, Royston MC, Reynolds GP, Cross AJ (1989) Frontal-cortical and left temporal glutamatergic dysfunction in schizophrenia. J Neurochem 52: 1781–1786PubMedCrossRefGoogle Scholar
  54. De Keyser J, Claeys A, De Backer J-P, Ebinger G, Roels F, Vanguelin G (1988) Autoradiographic localization of the D1 and D2 dopamine receptors in human brain. Neurosci Lett 91: 142–147PubMedCrossRefGoogle Scholar
  55. del Rio J, Fuentes JA (1969) Further studies on the antagonism of stereotyped behavior induced by amphetamine. Eur J Pharmacol 8: 73–78PubMedCrossRefGoogle Scholar
  56. Delay J, Deniker P, Harl JM (1952) Utilization en thérapeutique psychiatrique d’une phénothiazine d’action centrale élective (4560 RP). Ann Méd Psychol 110: 112–117Google Scholar
  57. Delay J, Deniker P, Tardieu Y, Lemperiere T (1955) Premiers essais de la réserpine. Presse Méd 63: 663–665PubMedGoogle Scholar
  58. Deniker P (1960) Experimental neurological syndromes and the new drug therapies in psychiatry. Compr Psychiatry 1: 92–102PubMedCrossRefGoogle Scholar
  59. Deutch AY, Roth RH (1988) Alterations in dopamine synthesis induced by chronic neuroleptic administration: a possible biochemical correlate of depolarization inactivation. Soc Neurosci Abstr 14: 27Google Scholar
  60. Di Chiara G, Porceddu ML, Spano PF, Gessa GL (1977) Haloperidol increases and apomorphine decreases striatal dopamine metabolism after destruction of striatal dopamine-sensitive adenylate-cyclase by kainic acid. Brain Res 130: 374–382PubMedCrossRefGoogle Scholar
  61. Doherty MD, Gratton A (1991) Behavioral evidence of depolarization block of mesencephalic dopamine neurons by acute haloperidol in partially 6hydroxydopamine lesioned rats. Behav Neurosci 105: 579–587PubMedCrossRefGoogle Scholar
  62. Doucet G, Descarries I, Garcia S (1986) Quantification of the dopamine innervation in adult rat neostriatum. Neuroscience 19: 427–445PubMedCrossRefGoogle Scholar
  63. Ewing AG, Wightman RM (1984) Monitoring the stimulated release of dopamine with in vivo voltammetry. II. Clearance of released dopamine from extracellular fluid. J Neurochem 43: 570–577PubMedCrossRefGoogle Scholar
  64. Fann WE, Lake CR (1976) Amantadine versus trihexylphenidyl in the treatment of neuroleptic-induced parkinsonism. Am J Psychiatry 8: 940–943Google Scholar
  65. Fardé L, Wiesel FA, Nordstrom A-L, Sedvall G (1989) D1-and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology 99: S28 - S31PubMedCrossRefGoogle Scholar
  66. Farnebo LO, Hamberger B (1971) Drug-induced changes in the release of 3H-monoamines from field-stimulated rat brain slices. Acta Physiol Scand [Suppl] 371: 35–44CrossRefGoogle Scholar
  67. Fibiger HC, LePiane FG, Jakubovic A, Phillips AG (1987) The role of dopamine in intracranial self-stimulation of the ventral tegmental area. J Neurosci 7: 3888–3896PubMedGoogle Scholar
  68. Finlay JM, Jakubovic A, Fu DS, Fibiger HC (1987) Tolerance to haloperidol-induced increases in dopamine and metabolites: fact or artifact? Eur J Pharmacol 137: 117–121PubMedCrossRefGoogle Scholar
  69. Floran B, Silva I, Nava C, Aceves J (1988) Presynaptic modulation of the release of GABA by GABAA receptors in pars compacta and by GABAB receptors in pars reticulata of the rat substantia nigra. Eur J Pharmacol 150: 277–286PubMedCrossRefGoogle Scholar
  70. Flugel P (1956) Therapeutique par medication neuroleptiques obtenu en realizant systematique des etats Parkinsoniformes. Encéphale 45: 1090–1092PubMedGoogle Scholar
  71. Frey JM, Ticku MK, Huffman RD (1987) GABAergic supersensitivity within the pars reticulata of the rat substantia nigra following chronic haloperidol administration. Brain Res 425: 73–84PubMedCrossRefGoogle Scholar
  72. Frey JM, Ticku MK, Bell RD, Huffman RD (1989) Chronic haloperidol administration increases GABA binding and enhances neuronal responsiveness to iontophoresed GABA in rat globus pallidus. Brain Res 491: 57–67PubMedCrossRefGoogle Scholar
  73. Friedhoff AJ, Miller JC (1983) Clinical implications of receptor sensitivity modification. Annu Rev Neurosci 6: 121–148PubMedCrossRefGoogle Scholar
  74. Friedhoff AJ, Bonnet K, Rosengarten H (1977) Reversal of two manifestations of dopamine receptor supersensitivity by administration of L-dopa. Res Commun Chem Pathol Pharmacol 116: 411–423Google Scholar
  75. Gale K (1980) Chronic blockade of dopamine receptors by antischizophrenic drugs enhances GABA binding in substantia nigra. Nature (London) 283: 569–570CrossRefGoogle Scholar
  76. Garcia-Munoz M, Nicolaou NM, Tulloch IF, Wright AK, Arbuthnot GW (1977) Feedback loop or output pathway in striatonigral fibers? Nature (London) 265: 363–365CrossRefGoogle Scholar
  77. Geffen LB, Jessell TM, Cuello AC, Iversen LL (1976) Release of dopamine from dendrites in substantia nigra. Nature 260: 258–260PubMedCrossRefGoogle Scholar
  78. Gerlach J, Luhdorf K (1975) The effect of L-DOPA on young patients with simple schizophrenia treated with neuroleptic drugs: a double-blind crossover trial with madopar and placebo. Psychopharmacology 44: 105–110CrossRefGoogle Scholar
  79. Giralt MT, Bonanno G, Raiteri M (1990) GABA terminal autoreceptors in the pars compacta and in the pars reticulata of the rat substantia nigra are GABAB. Eur J Pharmacol 175: 137–144PubMedCrossRefGoogle Scholar
  80. Glazer WM, Bowers JB Jr, Charney DS, Heninger GR (1989) The effect of neuroleptic discontinuation on psychopathology, involuntary movements, and biochemical measures in patients with persistent tardive dyskinesia. Biol Psychiatry 26: 224–233PubMedCrossRefGoogle Scholar
  81. Glowinski J, Axelrod J, Iversen LL (1966) Regional studies of catecholamines in the rat brain. IV. Effects of drugs on the disposition and metabolism of 3Hnorepinephrine and 3H-dopamine. J Pharmacol Exp Ther 153: 30–41PubMedGoogle Scholar
  82. Glowinski J, Chéramy A, Romo R, Barbeito L (1988) Presynaptic regulation of dopaminergic transmission in the striatum. Cell Mol Neurobiol 8: 7–17PubMedCrossRefGoogle Scholar
  83. Goldstein JM, Litwin LC (1988) Spontaneous activity of A9 and A10 dopamine neurons after acute and chronic administration of the selective dopamine D-1 receptor antagonist SCH23390. Eur J Pharmacol 155: 175–180PubMedCrossRefGoogle Scholar
  84. Gonon FG (1988) Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopaminergic neurons as studied by in vivo electrochemistry. Neuroscience 24: 19–28PubMedCrossRefGoogle Scholar
  85. Grace AA (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41: 1–24PubMedCrossRefGoogle Scholar
  86. Grace AA, Bunney BS (1979) Paradoxical GABA excitation of nigral dopaminergic cells: indirect mediation through reticulata inhibitory neurons. Eur J Pharmacol 59: 211–218PubMedCrossRefGoogle Scholar
  87. Grace AA, Bunney BS (1980a) Nigral dopamine neurons: intracellular recording and identification with L-DOPA injection and histofluorescence. Science 210: 654–656PubMedCrossRefGoogle Scholar
  88. Grace AA, Bunney BS (1980b) Effects of baclofen on nigral dopaminergic cell activity following acute and chronic haloperidol treatment. Brain Res Bull 5 [Suppl] 2: 537–543Google Scholar
  89. Grace AA, Bunney BS (1983a) Intracellular and extracellular electrophysiology of nigral dopamine neurons. I. Identification and characterization. Neuroscience 10: 301–315PubMedCrossRefGoogle Scholar
  90. Grace AA, Bunney BS (1983b) Intracellular and extracellular electrophysiology of nigral dopaminergic neurons. II. Action potential generating mechanisms and morphological correlates. Neuroscience 10: 317–331PubMedCrossRefGoogle Scholar
  91. Grace AA, Bunney BS (1983c) Intracellular and extracellular electrophysiology of nigral dopaminergic neurons. III. Evidence for electrotonic coupling. Neuroscience 10: 333–348PubMedCrossRefGoogle Scholar
  92. Grace AA, Bunney BS (1984a) The control of firing pattern in nigral dopamine neurons: single spike firing. J Neurosci 4: 2866–2876PubMedGoogle Scholar
  93. Grace AA, Bunney BS (1984b) The control of firing pattern in nigral dopamine neurons: burst firing. J Neurosci 4: 2877–2890PubMedGoogle Scholar
  94. Grace AA, Bunney BS (1985a) Opposing effects of striatonigral feedback pathways on midbrain dopamine cell activity. Brain Res 333: 271–284PubMedCrossRefGoogle Scholar
  95. Grace AA, Bunney BS (1985b) Low doses of apomorphine elicit two opposing influences on dopamine cell electrophysiology. Brain Res 333: 285–298PubMedCrossRefGoogle Scholar
  96. Grace AA, Bunney BS (1986) Induction of depolarization block in midbrain dopamine neurons by repeated administration of haloperidol: analysis using in vivo intracellular recording. J Pharmacol Exp Ther 238: 1092–1100PubMedGoogle Scholar
  97. Gratton A, Hoffer BJ, Gerhardt GA (1988) Effects of electrical stimulation of brain reward sites on release of dopamine in rat: an in vivo electrochemical study. Brain Res Bull 21: 319–324PubMedCrossRefGoogle Scholar
  98. Groves PM, Wilson CJ, Young SJ, Rebec GV (1975) Self-inhibition of dopaminergic neurons. Science 190: 522–529PubMedCrossRefGoogle Scholar
  99. Guidotti A, Gale K, Toffano G, Vargas FM (1978) Tolerance to tyrosine hydroxylase activation in n. accumbens and c. striatum after repeated injections of “classical” and “atypical” antischizophrenic drugs. Life Sci 23: 501–506PubMedCrossRefGoogle Scholar
  100. Hechler V, Gobaille S, Bourguignon J-J, Maitre M (1991) Extracellular events induced by y-hydroxybutyrate in striatum: a microdialysis study. J Neurochem 56: 938–944PubMedCrossRefGoogle Scholar
  101. Heffner TG, Zigmond MJ, Stricker EM (1977) Effects of dopaminergic agonists and antagonists on feeding in intact and 6-hydroxydopamine-treated rats. J Pharmacol Exp Ther 201: 386–399PubMedGoogle Scholar
  102. Herrling PL (1985) Pharmacology of the corticocaudate excitatory postsynaptic potential in the cat: evidence for its mediation by quisqualate or kainate receptors. Neuroscience 14: 417–426PubMedCrossRefGoogle Scholar
  103. Hollerman JR, Grace AA (1989a) Acute haloperidol administration induces depolarization block of nigral dopamine neurons in rats after partial dopamine lesions. Neurosci Lett 96: 82–88PubMedCrossRefGoogle Scholar
  104. Hollerman JR, Grace AA (1989b) Altered responsiveness to haloperidol following partial dopamine depletion in rats: behavioral and electrophysiological aspects. Soc Neurosci Abstr 15: 1002Google Scholar
  105. Hollerman JR, Abercrombie ED, Grace AA (1992) Electrophysiological, biochemical, and behavioral studies of acute haloperidol-induced depolarization block of nigral dopamine neurons. Neuroscience 47: 589–601PubMedCrossRefGoogle Scholar
  106. Ichikawa J, Meltzer HY (1991) Differential effects of repeated treatment with haloperidol and clozapine on dopamine release and metabolism in the striatum and the nucleus accumbens. J Pharmacol Exp Ther 256: 348–357PubMedGoogle Scholar
  107. Imperato I, DiChiara G (1985) Dopamine release and metabolism in awake rats after systemic neuroleptics as studied by trans-striatal dialysis. J Neurosci 5: 297–306PubMedGoogle Scholar
  108. Imperato A, Honoré T, Jensen LH (1990) Dopamine release in the nucleus caudatus and accumbens is under glutamatergic control through non-NMDA receptors: a study in freely-moving rats. Brain Res 530: 223–228PubMedCrossRefGoogle Scholar
  109. Ingvar DH, Franzen G (1974) Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenia. Acta Psychiatr Scand 50: 425–462PubMedCrossRefGoogle Scholar
  110. Invernizzi R, Morali F, Pozzi L, Samanin R (1990) Effects of acute and chronic clozapine on dopamine release and metabolism in the striatum and nucleus accumbens of conscious rats. Br J Pharmacol 100: 744–748Google Scholar
  111. Iversen LL, Rogawski MA, Miller RJ (1976) Comparison of the effects of neuroleptic drugs on pre-and postsynaptic dopaminergic mechanisms in the rat striatum. Mol Pharmacol 12: 251–262PubMedGoogle Scholar
  112. Iwatsubo K, Clouet D (1977) Effects of morphine and haloperidol on the electrical activity of rat nigrostriatal neurons. J Pharmacol Exp Ther 202: 429–436PubMedGoogle Scholar
  113. Janssen AJ, Niemegeers CJE, Schellekens KHL (1965) Is it possible to predict the clinical effects of neuroleptic drugs (major tranquilizers) from animal data? Drug Res (Arzneimittelforschung) I15: 104–177Google Scholar
  114. Javitt DC (1987) Negative symptomatology and the PCP (phencyclidine) model of schizophrenia. Hillside J Clin Psychiat 9: 12–35Google Scholar
  115. Jiang LH, Tsai M, Wang RY (1988) Chronic treatment with high doses of haloperidol fails to decrease the time course for the development of depolarization inactivation of midbrain dopamine neurons. Life Sci 43: 75–81PubMedCrossRefGoogle Scholar
  116. Kabzinski AM, Szewczak MR, Cornfeldt ML, Fielding S (1987) Differential effects of dopamine agonists and antagonists on the spontaneous electrical activity of A9 and A10 dopamine neurons. Soc Neurosci Abstr 13: 908Google Scholar
  117. Kamata K, Sugimoto A, Kameyama T (1986) Effect of chronic haloperidol on dopamine release following microinjection of GABA into the substantia nigra zona reticulata in the rat. Brain Res 380: 1–6PubMedCrossRefGoogle Scholar
  118. Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic: a double-blind comparison versus chlorpromazine/benztropine. Arch Gen Psychiatry 45: 789–796PubMedCrossRefGoogle Scholar
  119. Kebabian JW, Calne R (1979) Multiple receptors for dopamine. Nature 277: 93–96PubMedCrossRefGoogle Scholar
  120. Keefe KA, Stricker EM, Zigmond MJ, Abercrombie ED (1990) Environmental stress increases extracellular dopamine in striatum of 6-hydroxydopamine-treated rats: in vivo microdialysis studies. Brain Res 527: 350–353PubMedCrossRefGoogle Scholar
  121. Kehr W, Carlsson A, Lindqvist M, Magnusson T, Atack C (1972) Evidence for a receptor-mediated feedback control of striatal tyrosine hydroxylase. J Pharm Pharmacol 24: 744–747PubMedCrossRefGoogle Scholar
  122. Keller RW, Duhr WG, Wightman RM, Zigmond MJ (1988) The effect of L-DOPA on in vivo dopamine release from nigrostriatal bundle neurons. Brain Res 447: 191–194PubMedCrossRefGoogle Scholar
  123. Kim JS, Kornhuber HH, Schmid-Burgk W, Holzmiller B (1980) Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis of schizophrenia. Neurosci Lett 20: 379–382PubMedCrossRefGoogle Scholar
  124. Klein DE, Davis JM (1969) Diagnosis and drug treatment of psychiatric disorders. Williams & Wilkins, Baltimore MDGoogle Scholar
  125. Kondo Y, Iwatsubo K (1980) Diminished responses of nigral dopaminergic neurons to haloperidol and morphine following lesions in the striatum. Brain Res 181: 237–240PubMedCrossRefGoogle Scholar
  126. Korf J, Venema K (1985) Amino acids in rat striatal dialysates: methodological aspects and changes after electroconvulsive shock J Neurochem 45: 1341–1348PubMedCrossRefGoogle Scholar
  127. Korf J, Zielman M, Westerink BHC (1976) Dopamine release in substantia nigra. Nature 260: 257–258PubMedCrossRefGoogle Scholar
  128. Kuhr WG, Wightman RM (1986) Real-time measurement of dopamine release in rat brain. Brain Res 381: 168–171PubMedCrossRefGoogle Scholar
  129. Kuhr WG, Ewing AG, Caudill WL, Wightman RM (1984) Monitoring the stimulated release of dopamine with in vivo voltammetry. I. Characterization of the response observed in the caudate nucleus of the rat. J Neurochem 43: 560–569PubMedCrossRefGoogle Scholar
  130. Kuhr WG, Ewing AG, Near JA, Wightman RM (1985) Amphetamine attenuates the stimulated release of dopamine in vivo. J Pharmacol Exp Ther 232: 388–394PubMedGoogle Scholar
  131. Laborit H, Huguenard P, Alluaume R (1952) Un nouveau stabilisateur végétatif, le 4560 RP. Presse Méd 60: 206PubMedGoogle Scholar
  132. Lane RF, Blaha CD (1987) Chronic haloperidol decreases dopamine release in striatum and nucleus accumbens in vivo: depolarization block as a possible mechanism of action. Brain Res Bull 18: 135–138PubMedCrossRefGoogle Scholar
  133. Lavy S, Melamed E, Penchas S (1978) Tardive dyskinesia associated with metoclopramide. Br Med J 1: 77–78PubMedCrossRefGoogle Scholar
  134. Leviel V, Gobert A, Guibert B (1990) The glutamate-mediated release of dopamine in the rat striatum: Further characterization of the dual excitatory-inhibitory function. Neuroscience 39: 305–312PubMedCrossRefGoogle Scholar
  135. Leysen JE (1982) Review on neuroleptic receptors; specificity and multiplicity of in vitro binding relates to pharmacological activity. In: Usdin E, Dahl S, Gram LF, Lingjaerde O (eds) Clinical pharmacology in psychiatry: neuroleptic and antidepressant research. Macmillan, Basingstoke Hants, pp 35–47Google Scholar
  136. Lidow MS, Goldman-Rakic, PS, Rakic P, Innis RB (1989) Dopamine D, receptors in the cerebral cortex: distribution and pharmacological characterization with [3H]raclopride. Proc Natl Acad Sci USA 86: 6412–6416PubMedCrossRefGoogle Scholar
  137. Lindstrom LH (1985) Low HVA and normal 5-HIAA CSF levels in drug-free schizophrenic patients compared to healthy volunteers: correlations to symptomatology and family history. Psychiatry Res 14: 265–273PubMedCrossRefGoogle Scholar
  138. Lloyd KG, Davidson L, Hornykiewicz O (1975) The neurochemistry of Parkinson’s disease: effect of L-dopa therapy. J Pharmacol Exp Ther 195: 453–464PubMedGoogle Scholar
  139. Maas JW (1979) Neurotransmitters and depression. Too much, too tittle, or too unstable? Trends Neurosci 2: 306–308CrossRefGoogle Scholar
  140. Manos N, Gziouzepas J, Logothetis J (1981) The need for continuous use of antiparkinsonian medication with chronic schizophrenic patients receiving longterm neuroleptic therapy. Am J Psychiatry 138: 184–188PubMedGoogle Scholar
  141. Marsden CD, Tarsy D, Baldessarini RJ (1975) Spontaneous and drug-induced movement disorders in psychotic patients. In: Benson DF, Blumer D (eds) Psychiatric aspects of neurologic disease. Grune & Stratton, New York, pp 219–266Google Scholar
  142. Matthysse S (1973) Antipsychotic drug actions: a clue to the neuropathology of schizophrenia? Fed Proc 32: 200–205PubMedGoogle Scholar
  143. May PRA, Tuma AH, Yale C, Potepam, P, Dixon WJ (1976) Schizophrenia: a follow-up study of results of treatment, hospital stay over two to five years. Arch Gen Psychiatry 33: 481–506PubMedCrossRefGoogle Scholar
  144. May LJ, Kuhr WG, Wightman RM (1988) Differentiation of dopamine overflow and uptake processes in the extracellular fluid of the rat caudate nucleus with fast-scan in vivo voltammetry. J Neurochem 51: 1060–1069PubMedCrossRefGoogle Scholar
  145. McGeorge AJ, Faull RLM (1989) The organization of the projection from the cerebral cortex to the striatum in the rat. Neuroscience 29: 503–537PubMedCrossRefGoogle Scholar
  146. Meltzer HY (1984) Dopamine and negative symptoms in schizophrenia: critique of the type I-II hypotheses. In: Alpert M (ed) Controversies in schizophrenia: changes and consistencies. Guilford Press, New York, pp 110–144Google Scholar
  147. Meltzer HY (1989) Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology 99 [Suppl]: S18 - S32PubMedCrossRefGoogle Scholar
  148. Meltzer HY (1991) The mechanism of action of novel antipsychotic drugs. Schizophr Bull 17: 263–287PubMedGoogle Scholar
  149. Meltzer HY, Sommers AA, Luchins DJ (1986) The effect of neuroleptics and other psychotropic drugs on negative symptoms in schizophrenia. J Clin Pharmacol 6: 329–338Google Scholar
  150. Meltzer LT, Christoffersen CL, Heffner TG, Freeman AS, Chiodo LA (1989) CI-943, a potential antipsychotic agent. III. Evaluation of effects on dopamine neuronal activity. J Pharmacol Exp Ther 251: 123–130PubMedGoogle Scholar
  151. Mercuri NB, Calabresi P, Bernardi G (1990) Responses of rat substantia nigra compacta neurones to L-DOPA. Br J Pharmacol 100: 257–260PubMedGoogle Scholar
  152. Mishra RK, Marshall AM, Varmuza SL (1980) Supersensitivity in rat caudate nucleus: effects of 6-hydroxydopamine on the time course of dopamine receptor and cyclic AMP changes. Brain Res 200: 47–57PubMedCrossRefGoogle Scholar
  153. Moghaddam B, Gruen RJ (1991) Do endogenous excitatory amino acids influence striatal dopamine release? Brain Res 544: 329–330PubMedCrossRefGoogle Scholar
  154. Moghaddam B, Gruen RJ, Roth RH, Bunney BS, Adams RN (1990) Effect of L-glutamate on the release of striatal dopamine: in vivo dialysis and electrochemical studies. Brain Res 518: 55–60PubMedCrossRefGoogle Scholar
  155. Munkvad I, Pakkenberg H, Randrup A (1968) Aminergic systems in basal ganglia associated with stereotyped hyperactive behavior and catalepsy. Behav Brain Evol 1: 89–100CrossRefGoogle Scholar
  156. Nakahara D, Ozaki N, Kapoor V, Nagatsu T (1989) The effect of uptake inhibition on dopamine release from the nucleus accumbens of rats during self-or forced stimulation of the medial forebrain bundle. A microdialysis study. Neurosci Lett 104: 136–140CrossRefGoogle Scholar
  157. Nieoullon A, Chéramy A, Glowinski J (1978) Release of dopamine evoked by electrical stimulation of the motor and visual areas of the cerebral cortex in both caudate nuclei and in the substantia nigra in the cat. Brain Res 145: 69–83PubMedCrossRefGoogle Scholar
  158. Nisenbaum ES, Stricker EM, Zigmond MT, Berger TW (1986) Long-term effects of dopamine-depleting brain lesions on spontaneous activity of type II striatal neurons: relation to behavioral recovery. Brain Res 398: 221–230PubMedCrossRefGoogle Scholar
  159. Nisenbaum ES, Berger TW, Grace AA (1991) GABAB receptors reduce both glutamatergic excitation and GABAergic inhibition of striatal neurons through presynaptic mechanisms. Soc Neurosci Abstr 17: 850Google Scholar
  160. Nishikawa T, Takashima M, Toru M (1983a) Increased [3H]kainic acid binding in the prefrontal cortex in schizophrenia. Neurosci Lett 40: 245–250PubMedCrossRefGoogle Scholar
  161. Nishikawa R, Tanaka M, Koga I, Uchida Y (1983b) Combined treatment of tardive dyskinesia with clonidine and neuroleptics: a follow-up study of three cases for three years. Psychopharmacology 80: 374–375PubMedCrossRefGoogle Scholar
  162. Nowycky MC, Roth RH (1977) Presynaptic dopamine receptors. Development of supersensitivity following treatment with fluphenazine decanoate. Naunyn-, Schmiedebergs Arch Pharmacol 300: 247–254Google Scholar
  163. Nybâck H, Berggen BM, Hindmarsh T, Sedvall G, Weisel FA (1983) Cerebroventricular size and cerebrospinal fluid monoamine metabolites in schizophrenic patients and healthy volunteers. Psychiatry Res 9: 301–308PubMedCrossRefGoogle Scholar
  164. O’Neill RD, Gonzalez-Mora JL, Boutelle MG, Ormonde DE, Lowry JP, Duff A, Fumero B, Fillenz M, Mas M (1991) Anomalously high concentrations of brain extracellular uric acid detected with chronically implanted probes — Implications for in vivo sampling techniques. J Neurochem 57: 22–29PubMedCrossRefGoogle Scholar
  165. Pani L, Gessa GL, Carboni S, Portas CM, Rossetti ZL (1990) Brain dialysis and dopamine: does the extracellular concentration of dopamine reflect synaptic release? Eur J Pharmacol 180: 85–90PubMedCrossRefGoogle Scholar
  166. Peroutka SJ, Snyder SH (1980) Relationship of neuroleptic drug effects at brain dopamine, serotonin, a-adrenergic, and histamine receptors to clinical potency. Am J Psychiatry 137: 1518–1522PubMedGoogle Scholar
  167. Perry TL (1982) Normal cerebrospinal fluid and brain glutamate levels in schizophrenia do not support the hypothesis of glutamatergic neuronal dysfunction. Neurosci Lett 28: 81–85PubMedCrossRefGoogle Scholar
  168. Pettegrew JW, Keshavan MS, Panchalingam K, Strychor S, Kaplan DB, Tretta M, Allen M (1991) Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. Arch Gen Psychiatry 48: 563–568PubMedCrossRefGoogle Scholar
  169. Pickar D, Labarca R, Linnoila M, Roy A, Hommer D, Everett D, Paul SM (1984) Neuroleptic-induced decrease in plasma HVA and antipsychotic activity in schizophrenic patients. Science 225: 954–957PubMedCrossRefGoogle Scholar
  170. Pickar D, Labarca R, Doran AR, Wolkowitz OM, Roy A, Breier A, Linnoila M, Paul SM (1986) Longitudinal measurement of plasma homovanillic acid levels in schizophrenic patients. Arch Gen Psychiatry 43: 669–676PubMedCrossRefGoogle Scholar
  171. Post RM, Fink E, Carpenter WT, Goodwin FK (1975) Cerebrospinal fluid amine metabolites in acute schizophrenia. Arch Gen Psychiatry 32: 1063–1069PubMedCrossRefGoogle Scholar
  172. Pucak ML, Grace AA (1991a) Partial dopamine depletions result in an enhanced sensitivity of residual dopamine neurons to apomorphine. Synapse 9: 144–155PubMedCrossRefGoogle Scholar
  173. Pucak ML, Grace AA (1991b) Blockade of somatodendritic autoreceptors on nigral dopamine neurons contributes to the firing rate-increasing effects of dopamine antagonists. Soc Neurosci Abstr 17: 1352Google Scholar
  174. Randrup A, Munkvad I (1965) Special antagonism of amphetamine-induced abnormal behaviour. Psychopharmacologia 7: 416–422PubMedCrossRefGoogle Scholar
  175. Reimann W, Zumstein A, Jackisch R, Starke K, Hertting G (1979) Effect of extracellular dopamine on the release of dopamine in the rabbit caudate nucleus: evidence for a dopaminergic feed-back inhibition. Naunyn-Schmiedebergs Arch Pharmacol 306: 53–60PubMedCrossRefGoogle Scholar
  176. Reivich M, Kuhl D, Wolf A, Greenberg J, Phelps M, Ido T, Casella V, Fowler J, Hoffman E, Alavi A, Som P, Sokoloff L (1979) The (18F) fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man. Circ Res 44: 127–137PubMedGoogle Scholar
  177. Richfield EK, Penney JB, Young AB (1989) Anatomical and affinity state comparisons between dopamine D1 and D2 receptors in the rat central nervous system. Neuroscience 30: 767–777PubMedCrossRefGoogle Scholar
  178. Roberts GW, Bruton CJ (1990) Notes from the graveyard: neuropathology and schizophrenia. Neuropathol Appl Neurobiol 16: 3–16PubMedCrossRefGoogle Scholar
  179. Robinson TE, Whishaw IQ (1988) Normalization of extracellular dopamine in striatum following recovery from a partial unilateral 6-OHDA lesion of the substantia nigra: a microdialysis study in freely moving rats. Brain Res 450: 209–224PubMedCrossRefGoogle Scholar
  180. Romo R, Chéramy A, Godeheu G, Glowinski J (1986) In vivo presynaptic control of dopamine release in the cat caudate nucleus. I. Opposite changes in neuronal activity and release evoked from thalamic motor nuclei. Neuroscience 19: 1067–1079PubMedCrossRefGoogle Scholar
  181. Rompré P-P, Wise RA (1989) Behavioral evidence for midbrain dopamine neuron depolarization block. Brain Res 477: 152–156PubMedCrossRefGoogle Scholar
  182. Sah P, Hestrin S, Nicoll RA (1989) Tonic activation of NMDA receptors by ambient glutamate enhances excitability of neurons. Science 246: 815–818PubMedCrossRefGoogle Scholar
  183. Sands SB, Barish ME (1989) A quantitative description of excitatory amino acid neurotransmitter responses on cultured embryonic Xenopus spinal neurons. Brain Res 502: 375–386PubMedCrossRefGoogle Scholar
  184. Scatton B, Worms P (1978) Subsensitivity of striatal and mesolimbic dopamine target cells after repeated treatment with apomorphine dipivaloyl ester. NaunynSchmiedebergs Arch Pharmacol 303: 271–278PubMedGoogle Scholar
  185. Sedvall G, Farde L, Persson A, Weisel FA (1986) Imaging of neurotransmitter receptors in the living human brain. Arch Gen Psychiatry 43: 995–1006PubMedCrossRefGoogle Scholar
  186. Seeman P, Chau-Wong M, Tedesco J, Wong K (1975) Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc Natl Acad Sci USA 72: 4376–4380PubMedCrossRefGoogle Scholar
  187. Seeman P, Lee T, Chau-Wong M, Wong K (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature (London) 261: 717–719CrossRefGoogle Scholar
  188. Seeman P, Bzowej NJ, Guan HC, Bergeron C, Reynolds GP, Bird ED, Riederer P, Jellinger K, Tourtelotte WW (1987) Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer’s, Parkinson’s and Huntington’s diseases. Neuropsychopharmacology 1: 5–15PubMedCrossRefGoogle Scholar
  189. Serrano A, D’Angio M, Scatton B (1989) NMDA antagonists block restraint-induced increase in extracellular DOPAC in rat nucleus accumbens. Eur J Pharmacol 162: 157–166PubMedCrossRefGoogle Scholar
  190. Shalaby I, Spear LP (1980) Psychopharmacological effects of low and high doses of apomorphine during ontogeny. Eur J Pharmacol 67: 451–459PubMedCrossRefGoogle Scholar
  191. Sharp T, Zetterstrom T, Ungerstedt U (1986) An in vivo study of dopamine release and metabolism in rat brain regions using intracerebral dialysis. J Neurochem 47: 113–122PubMedCrossRefGoogle Scholar
  192. Shelton RC, Karson CN, Doran AR, Pickar D, Bigelow LB, Weinberger DR (1988) Cerebral structural pathology in schizophrenia: evidence for a selective prefrontal cortical defect. Am J Psychiatry 145: 154–163PubMedGoogle Scholar
  193. Sherman AD, Davidson AT, Baruah S, Hegwood TS, Waziri R (1991) Evidence of glutamatergic deficiency in schizophrenia. Neurosci Lett 121: 77–80PubMedCrossRefGoogle Scholar
  194. Siever LJ, Davis KL (1985) Overview: toward a dysregulation hypothesis of depression. Am J Psychiatry 142: 1017–1031PubMedGoogle Scholar
  195. Skarsfeldt T (1988) Differential effects after repeated treatment with halopoeridol, clozapine, thioridazine, and tefludazine on SNC and VTA dopamine neurons in rats. Life Sci 42: 1037–1044PubMedCrossRefGoogle Scholar
  196. Skirboll LR, Grace AA, Bunney BS (1979) Dopamine auto-and postsynaptic receptors: electrophysiological evidence for differential sensitivity to dopamine agonists. Science 206: 80–82PubMedCrossRefGoogle Scholar
  197. Sneed OC, Bearden LJ (1980) Naloxone overcomes the dopaminergic, EEG, and behavioral effects of y-hydroxybutyrate. Neurology 30: 832–838Google Scholar
  198. Snell LD, Johnson KM (1985) Antagonism of N-methyl-D-aspartate-induced transmitter release in the rat striatum by phencyclidine-like drugs and its relationship to turning behavior. J Pharmacol Exp Ther 235: 50–57PubMedGoogle Scholar
  199. Snyder SH (1972) Catecholamines in the brain are mediators of amphetamine psychosis. Arch Gen Psychiatry 27: 169–179PubMedCrossRefGoogle Scholar
  200. Snyder SH (1973) Amphetamine psychosis: a model schizophrenia mediated by catecholamines, Am J Psychiatry 130: 61–67PubMedGoogle Scholar
  201. Snyder SH (1980) Biological aspects of mental disorders, chapter 5. Schizophrenia: etiology and treatment. Oxford University Press, New York, pp 58–68Google Scholar
  202. Snyder AM, Stricker EM, Zigmond MJ (1985) Stress-induced neurological impairments in an animal model of Parkinsonism. Ann Neurol 18; 544–551PubMedCrossRefGoogle Scholar
  203. 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 (London) 347: 146–151CrossRefGoogle Scholar
  204. Sorensen SM, Humphreys TM, Palfreyman MG (1989) Effect of acute and chronic MDL 73147EF, a 5-HT3 receptor antagonist, on A9 and A10 dopamine neurons. Eur J Pharmacol 163: 115–118PubMedCrossRefGoogle Scholar
  205. Spencer H (1976) Antagonism of cortical excitation of striatal neurones by glutamic acid diethylester: Evidence for glutamic acid as an excitatory transmitter in the rat striatum. Brain Res 102: 91–101PubMedCrossRefGoogle Scholar
  206. Stevens JR (1973) An anatomy of schizophrenia? Arch Gen Psychiatry 29: 177–189PubMedCrossRefGoogle Scholar
  207. Stevens JR (1991) Psychosis and the temporal lobe. In: Smith D, Treiman D, Trimble M (eds) Advances in neurology, vol 55. Raven Press, New York, pp 79–96Google Scholar
  208. Stille G, Hippius H (1971) Kritische Stellungsnahme zum Begriff der Neuroleptika (anhand von pharmakologischen and klinischen Befunden mit Clozapin). Pharmacopsychiatry 4: 182–191CrossRefGoogle Scholar
  209. Strecker RE, Jacobs BL (1985) Substantia nigra dopaminergic unit activity in behaving cats: effect of arousal on spontaneous discharge and sensory evoked activity. Brain Res 361: 339–350PubMedCrossRefGoogle Scholar
  210. Tamminga CA, Schaffer MH, Smith RC, Davis JM (1978) Schizophrenic symptoms improve with apomorphine. Science 200: 567–568PubMedCrossRefGoogle Scholar
  211. Taylor KM, Snyder SH (1971) Differential effects of d-and 1-amphetamine on behavior and on catecholamine disposition in dopamine and norepinephrine containing neurons of rat brain. Brain Res 28: 295–309PubMedCrossRefGoogle Scholar
  212. Torrey EF (1987) Prevalence studies in schizophrenia. Br J Psychiatry 150: 598–608PubMedCrossRefGoogle Scholar
  213. Tupin JP (1985) Focal neuroleptization: an approach to optimal dosing for initial and continuing therapy. J Clin Psychopharmacol 5 [Suppl] 3: 1521Google Scholar
  214. Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand 83 (S367): 95–122Google Scholar
  215. Ungerstedt U, Herrera-Marschnitz M, Jungnelius U, Stahle L, Tossman U, Zetterström T (1982) Dopamine synaptic mechanisms reflected in studies combining behavioral recordings and brain dialysis. Adv Biosci 37: 219–231Google Scholar
  216. Van Kammen DP, Mann LS, Sternberg DE, Scheinin M, Ninan PT, Marder SR, Van Kammen WB, Reider RO, Linnoila M (1983) Dopamine-ß-hydroxylase activity and homovanillic acid in spinal fluid of schizophrenic with brain atrophy. Science 220: 974–977PubMedCrossRefGoogle Scholar
  217. Van Kammen DP, Van Kammen WB, Mann LS, Seppala T, Linnoila M (1986) Dopamine metabolism in the cerebrospinal fluid of drug-free schizophrenic patients with and without cortical atrophy. Arch Gen Psychiatry 43: 978–983PubMedCrossRefGoogle Scholar
  218. Van Rossum JM (1966) The significance of dopamine-receptor blockade for the actions of neuroleptic drugs. Arch Int Pharmacodyn Thèr 160: 492–494PubMedGoogle Scholar
  219. Van Tol HHM, Bunzow JR, Guan H-C, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991) Cloning of the gene for a human D4 receptor with high affinity for the antipsychotic clozapine. Nature (London) 350: 610–614CrossRefGoogle Scholar
  220. Vickroy TW, Johnson KM (1983) Effects of phencyclidine on the release and synthesis of newly formed dopamine. Neuropharmacology 22: 839–842PubMedCrossRefGoogle Scholar
  221. Waldmeier PC (1991) The GABAB antagonist, CGP 35348, antagonizes the effects of baclofen, y-butyrolactone and HA 966 on rat striatal dopamine synthesis. NaunynSchmiedebergs Arch Pharmacol 343: 173–178CrossRefGoogle Scholar
  222. Weick BG, Engber TM, Susel Z, Chase TN, Walters JR (1990) Responses of substantia nigra pars reticulata neurons to GABA and SKF 38393 in 6hydroxydopamine-lesioned rats are differentially affected by continuous and intermittent levodopa administration. Brain Res 523: 16–22PubMedCrossRefGoogle Scholar
  223. Weinberger DR, Berman KF, Zec RF (1986) Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. Arch Gen Psychiatry 43: 114–124PubMedCrossRefGoogle Scholar
  224. White FJ, Wang RY (1983a) Comparison of the effects of chronic haloperidol treatment on A9 and A10 dopamine neurons in the rat. Life Sci 32: 983–993PubMedCrossRefGoogle Scholar
  225. White FJ, Wang RY (1983b) Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons. Science 221: 1054–1057PubMedCrossRefGoogle Scholar
  226. Williamson P, Drost D, Stanley J, Carr T, Morrison S, Merskey H (1991) Localized phosphorus 31 magnetic resonance spectroscopy in chronic schizophrenic patients and normal controls. Arch Gen Psychiatry 48: 578PubMedCrossRefGoogle Scholar
  227. Wood GD (1977) An adverse reaction to metoclopramide therapy. Br J Oral Surg 15: 278–280CrossRefGoogle Scholar
  228. Wuerthele SM, Freed WJ, Olson L, Morihisa J, Spoor L, Wyatt RJ, Hoffer BJ (1981) Effect of dopamine agonists and antagonists on the electrical activity of substantia nigra neurons transplanted into the lateral ventricle of the rat. Exp Brain Res 44: 1–10PubMedCrossRefGoogle Scholar
  229. Wyatt RJ (1991) Neuroleptics and the natural course of schizophrenia. Schizophr Bull 17: 325–351PubMedGoogle Scholar
  230. Zetterström T, Sharp T, Marsden CA, Ungerstedt U (1983) In vivo measurement of dopamine and its metabolites by intracerebral dialysis: changes after d-amphetamine. J Neurochem 41: 1769–1773PubMedCrossRefGoogle Scholar
  231. Zetterström T, Sharp T, Ungerstedt U (1984) Effect of neuroleptic drugs on striatal dopamine release and metabolism in the awake rat studied by intracerebral dialysis. Eur J Pharmacol 106: 27–37PubMedCrossRefGoogle Scholar
  232. Zetterström T, Sharp T, Ungerstedt U (1985) Effect of neuroleptic drugs on striatal dopamine release and metabolism in the awake rat studied by intracerebral dialysis. Eur J Pharmacol 106: 27–37CrossRefGoogle Scholar
  233. Zetterström T, Sharp T, Collin AK, Ungerstedt U (1988) In vivo measurement of extracellular dopamine and DOPAC in rat striatum after various dopamine-releasing drugs: implications for the origin of extracellular DOPAC. Eur J Pharmacol 148: 327–334PubMedCrossRefGoogle Scholar
  234. Zigmond MJ, Stricker EM (1973) Recovery of feeding and drinking by rats after intraventricular 6-hydroxydopamine or lateral hypothalamic lesions. Science 182: 717–720PubMedCrossRefGoogle Scholar
  235. Zigmond MJ, Berger TW, Grace AA, Stricker EM (1989) Compensatory responses to nigrostriatal bundle injury: studies with 6-hydroxydopamine in an animal model of Parkinsonism. Mol Chem Neuropathol 10: 185–200PubMedCrossRefGoogle Scholar
  236. Zigmond MJ, Abercrombie ED, Berger TW, Grace AA, Stricker EM (1990) Compensations after lesions of central dopaminergic neurons: some clinical and basic implications. Trends Neurosci 13: 290–296PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • A. A. Grace
    • 1
  1. 1.Departments of Behavioral Neuroscience and PsychiatryUniversity of PittsburghPittsburghUSA

Personalised recommendations