Clozapine: Mechanism of Action in Relation to its Clinical Advantages

  • Herbert Y. Meltzer
Part of the International Perspectives Series: Psychiatry, Psychology, and Neuroscience book series


Clozapine, a dibenzodiazepine, is the prototype of an atypical antipsychotic drug. A generally accepted definition of an atypical antipsychotic drug is one that produces weak catalepsy in rodents, minimal extrapyramidal side effects (EPS) at clinically effective doses, and minimal plasma prolactin (PRL) elevations in humans.1 Almost all such agents are dopamine (DA) receptor antagonists, and block stereotypy or locomotor activity in rodents due to stimulation of DA receptors by direct-acting DA agonists, (eg, apomorphine) or indirect DA agonists (eg, d-amphetamine). Atypical antipsychotic drugs block the conditioned avoidance response, another test which indicates their antipsychotic potential. Clozapine clearly fits this definition.1–3


Nucleus Accumbens Antipsychotic Drug Tardive Dyskinesia Dorsal Raphe Atypical Antipsychotic Drug 
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  1. 1.
    Meltzer HY: Clozapine: clinical advantages and biological mechanisms, in C Schulz, C Tamminga (eds): Schizophrenia: A Scientific Focus. New York, Oxford Press, 1989.Google Scholar
  2. 2.
    Berzewski H, Helmchen H, Hippius H, et al: Das Klinische werkungspek- trum eines neuen dibenzdiazepin-derivates. Arzneimittelforschung 1969; 19: 496–498.Google Scholar
  3. 3.
    Burki HR, Ruch W, Asper H: Effects of clozapine, thioridazine, perlapine and haloperidol on the metabolism of the biogenic amines in the brain of the rat. Psychopharmacologia 1975;41:27–33.PubMedGoogle Scholar
  4. 4.
    Angst J, Bente D, Berner P, et al: Das clinische Wirkungsbild von clozapine (untersuchung mit dem AMP-system). Pharmakopsychiatrie 1971;4:200–211.Google Scholar
  5. 5.
    Matz R, Rick W, Oh D, et al: Clozapine, a potential antipsychotic agent without extrapyramidal manifestations. Curr Ther Res 1954;16:687–695.Google Scholar
  6. 6.
    Bjerkenstedt L, Harnryd C, Grimm V, et al: A double-blind comparison of melperone and thiothixene in psychotic women using a new rating scale, the CPRS. Arch Psychiatr Nervenkraz 1978;226:157–172.Google Scholar
  7. 7.
    Woggon B, Angst J, Bartels M, et al: Antipsychotic efficacy of fluperlapine: an open multicenter trial. Neuropsychobiology 1984;11:116–120.PubMedGoogle Scholar
  8. 8.
    Young MA, Meltzer HY, Fang VS: RMI-81,582: a novel antipsychotic drug. Psychopharmacology 1980;67:101–106.PubMedGoogle Scholar
  9. 9.
    Meltzer HY, Luchins DJ: Effect of clozapine in severe tardive dyskinesia: a case report. J Clin Psychopharmacology 1984;4:316–322.Google Scholar
  10. 10.
    Cleghorn J, Honigfeld, G, Abuzzahab FS, et al: The risks and benefits of clozapine versus chlorpromazine. J Clin Psychopharmacol 1987;7:377–384.Google Scholar
  11. 11.
    Kane J, Honigfeld G, Singer J, et al: Clozapine for the treatment-resistant schizophrenic: a double-blind comparison versus chlorpromazine/benztropine. Arch Gen Psychiatry 1988;45:789–796.PubMedGoogle Scholar
  12. 12.
    Honigfeld G, Patin J, Singer J: Clozapine: antipsychotic activity in treatment-resistant schizophrenics. Adv Therapy 1984;1:77–97.Google Scholar
  13. 13.
    van Praag HM, Korf J, Dols, L: Clozapine versus perphenazine: the value of the biochemical mode of action of neuroleptics in predicting their therapeutic activity. Br J Psychiatry 1976;129:547–555.PubMedGoogle Scholar
  14. 14.
    Meltzer HY, Bastani B, Kwon K, et al: A prospective study of clozapine in treatment resistant schizophrenic patients: I: Preliminary report. Psychopharmacology, in press.Google Scholar
  15. 15.
    Juul Polvsen V, Noring V, Fog R, et al: Tolerability and therapeutic effect of clozapine: a retrospective investigation of 216 patients treated with clozapine for up to 12 years. Acta Psychiatr Scand 1985;71:176–185.Google Scholar
  16. 16.
    Kuha S, Meittenen E: Long-term effect of clozapine in schizophrenia: a retrospective study of 108 chronic schizophrenics treated with clozapine for up to 7 years. Nord Psychiatr Tidskr 1986;40:225–230.Google Scholar
  17. 17.
    Lindstrom LH: The effect of long-term treatment with clozapine in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years. Acta Psychiatr Scand 1988;77:524–529.PubMedGoogle Scholar
  18. 18.
    Meltzer HY, Goode DJ, Schyve PM, et al: Effect of clozapine on human serum prolactin levels. Am J Psychiatry 1979;136:1550–1555.PubMedGoogle Scholar
  19. 19.
    Amsler HA, Teerenhovi L, Barth E, et al: Agranulocytosis in patients treated with clozapine. A study of the Finnish epidemic. Acta Psychiat Scand 1977;56:241–248.PubMedGoogle Scholar
  20. 20.
    Koenig JI, Gudelsky GA, Meltzer HY: Stimulation of corticosterone and (3- endorphin secretion by selective 5-HT receptor subtype activation. Eur J Pharmacol 1987;137:1–8.PubMedGoogle Scholar
  21. 21.
    Imperato A, Angelucci L: Effects of the atypical neuroleptics clozapine and fluperlapine on the in vivo dopamine release in the dorsal striatum and in the prefrontal cortex. Abstracts of the XVI CINP Congress, Munich, 1988. Psychopharmacol 1988; 96 (suppl 1): 79.Google Scholar
  22. 22.
    Meltzer HY, Stahl SM: The dopamine hypothesis of schizophrenia: a review. Schiz Bull 1976;2:19–76.Google Scholar
  23. 23.
    Kebabian JW, Calne DB: Multiple receptors for dopamine. Nature 1979; 277:93–96.PubMedGoogle Scholar
  24. 24.
    Meltzer HY, Matsubara S, Lee J-C: Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-l, D-2, and serotonin2 pk; values. J. Pharm. Exp. Therap, in press.Google Scholar
  25. 25.
    Seeman P, Lee T, Chau-wong M, et al: Antipsychotic drug doses and neuro-leptic/dopamine receptors. Nature 1976;261:717–718.PubMedGoogle Scholar
  26. 26.
    Bartholini G, Haefely W, Jalfre M, et al: Effect of clozapine on cerebral catecholaminergic neurone systems. Br J Pharmacol 1972;46:736–740.PubMedGoogle Scholar
  27. 27.
    Burki HR, Ruch W, Asper H, et al: Effect of single and repeated administration of clozapine on the metabolism of dopamine and noradrenaline in the brain of the rat. Eur J Pharmacol 1974;27:180–190.PubMedGoogle Scholar
  28. 28.
    Waldmeier PC, Maitre L: Clozapine: reduction of the initial dopamine turnover increase by repeated treatment. Eur J Pharmacol 1976;38:197–203.PubMedGoogle Scholar
  29. 29.
    Anden NE, Stock G: Effect of clozapine on the turnover of dopamine in the corpus striatum and in the limbic system. J Pharmacy Pharmacol 1973;25: 346–348.Google Scholar
  30. 30.
    Zivkovic G, Guidotti A, Revuelta A, et al: Effect of thioridazine, clozapine, and other antipsychotics in the kinetic state of tyrosine hydroxylase and on the turnover state of dopamine in striatum and nucleus accumbens. J Pharmacol Exp Ther 1975;194:37–46.PubMedGoogle Scholar
  31. 31.
    Bartholini G, Keller HH, Pletscher A: Drug-induced changes of dopamine turnover in striatum and limbic system of the rat. J Pharm Pharmacol 1975;27:439–442.PubMedGoogle Scholar
  32. 32.
    Westernik BHC, Korf J: Influence of drugs on striatal and limbic homovanil- lic acid concentration in the rat brain. Eur J Pharmacol 1975;33:31–40.Google Scholar
  33. 33.
    Stawarz RJ, Hill H, Robinson SE, et al: On the significance of the increase in homovanillic acid (HVA) caused by antipsychotic drugs in corpus striatum and limbic forebrain. Psychopharmacologia (Berl) 1975;43:125–130.Google Scholar
  34. 34.
    Weisel FA, Sedvall G: Effects of antipsychotic drugs on homovanillic acid levels in striatum and olfactory tubercle of the rat. Eur J Pharmacol 1975;30:364–367.Google Scholar
  35. 35.
    Walters JR, Roth RH: Dopaminergic neurons: an in vivo system of measur¬ing drug interactions with presynaptic receptors. Naunyn-Schmeideherg s Arch Pharmacol 1976;296:5–14.Google Scholar
  36. 36.
    Wilk S, Watson E, Stanley ME: Differential sensitivity of two dopaminergic structures in rat brain to haloperidol and to clozapine. J Pharmacol Exp Ther 1975;195:265–270.PubMedGoogle Scholar
  37. 37.
    Waldmeier PC, Maitre L: On the relevance of preferential increases of meso- limbic versus striatal dopamine turnover for the prediction of antipsychotic activity of psychotropic drugs. J Neurochem 1976;27:589–587.PubMedGoogle Scholar
  38. 38.
    Maidment NT, Marsden C: Acute administration of clozapine, thioridazine and metoclopramide increases extracellular DOPAC and decreases extracellular 5-HIAA, measured in the nucleus accumbens and striatum of the rat using in vivo voltammetry. Neuropharmacology 1987;26:187–193.PubMedGoogle Scholar
  39. 39.
    Farde L, Wiesel F-A, Halldin C, et al: Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 1988;45:71–76.PubMedGoogle Scholar
  40. 41.
    Burt DR, Creese I. Snyder SH: Antischizophrenic drugs. Chronic treatment elevates dopamine receptor binding in brain. Science 1976;196:326–328.Google Scholar
  41. 41.
    Tarsy D, Baldessarini RJ: Behavioral supersensitivity to apomorphine following chronic treatment with drugs which interfere with the synaptic function of catecholamines. Neuropharmacology 1974;13:927–940.PubMedGoogle Scholar
  42. 42.
    Sayers AC, Burke AR, Ruch W, et al: Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesia: effect of clozapine, haloperidol, loxapine, and chlorpromazine. Psychopharmacology 1975;41:97–104.Google Scholar
  43. 43.
    Gnegy M, Uzunov P, Costa E: Participation of an endogenous Ca+ +-binding protein activator in the development of drug-induced supersensitivity of striatal dopamine receptors. J Pharmacol Exp Ther 1977;202:558–564.PubMedGoogle Scholar
  44. 44.
    Kobayashi RM, Fields JZ, Hrusck RE, et al: Brain neurotransmitter receptors and chronic antipsychotic drug treatment: a model for tardive dyskinesia, in Usdin E (ed): Animal Models in Psychiatry. New York, Pergamon Press, 1978, pp 405–409.Google Scholar
  45. 45.
    Racagni G, Bruno F, Bugatti A, et al: Behavioral and biochemical correlates after haloperidol and clozapine long-term treatment, in Catabeni G, Racagni G, Spano PF, Costa E (eds): Long-term Effects of Neuroleptics. Adv Bio-chem Psychopharmacol 1980;24:45–52.Google Scholar
  46. 46.
    Seeger TF, Thai L, Gardner EL: Behavioral and biochemical aspects of neuroleptic-induced dopaminergic supersensitivity. Studies with chronic clozapine and haloperidol. Psychopharmacology 1982;76:182–187.PubMedGoogle Scholar
  47. 47.
    Rupniak NMJ, Kilpatrick G, Hall MD, et al: Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol, sulpiride or clozapine in rats. Psychopharmacology 1984;84:512–519.PubMedGoogle Scholar
  48. 48.
    Smith RC, Davis JM: Behavioral evidence for supersensitivity after chronic administration of haloperidol. Life Sci 1976;19:725–732.PubMedGoogle Scholar
  49. 49.
    Allikmets LH, Zarkovsky AM, Nurk AM: Changes in catalepsy and receptor sensitivity following chronic neuroleptic treatment. Eur J Pharmacol 1981;75:145–147.PubMedGoogle Scholar
  50. 50.
    Rupniak NMJ, Hall MD, Kelly E, et al; Mesolimbic dopamine function is not altered during continuous or chronic tratment of rats with typical or atypical neuroleptic drugs. J Neural Transmission 1985;62:249–266.Google Scholar
  51. 51.
    Rupniak NMJ, Hall MD, Mann S, et al: Chronic treatment with clozapine unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat. Biochem Pharmacol 1985;34:2755–2763.PubMedGoogle Scholar
  52. 52.
    Chiodo LA, Bunney BS: Typical and atypical neuroleptics differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons. J. Neurosci 1983;3:1607–1619.PubMedGoogle Scholar
  53. 53.
    White FJ, Wang RY: Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine cells. Science 1983;221:1054–1057.PubMedGoogle Scholar
  54. 54.
    Hand TH, Hu X-T, Wang RY: Differential effects of acute clozapine and haloperidol on the activity of ventral tegmental (A 10) and nigrostriatal (A9) dopamine neurons. Brain Res 1987;415:257–269.PubMedGoogle Scholar
  55. 55.
    Souto M, Monti JM, Althier H: Effect of clozapine on the activity of central dopaminergic and noradrenergic neurons. Pharmacol Biochem Behavior 1979;10:5–9.Google Scholar
  56. 56.
    Huff R, Adams RN: Dopamine release in nucleus accumbens and striatum by clozapine: simultaneous monitoring by in vivo electrochemistry. Neuropharmacology 1980;19:587–590.PubMedGoogle Scholar
  57. 57.
    Lane RF, Blaha CD: Electrochemistry in vivo: application to CNS pharmacology. Ann NY Acad Sci 1986;473:50–69.PubMedGoogle Scholar
  58. 58.
    Blaha CD, Lane RF: Chronic treatment with classical and atypical antipsychotic drugs differentially decrease dopamine release in striatum and nucleus accumbens in vivo. Neurosci Lett 1987;78:188–204.Google Scholar
  59. 59.
    Chiodo LA, Bunney BS: Possible mechanisms by which repeated clozapine administration differentially affects the activity of two subpopulations of midbrain dopamine neurons. J Neuroscience 1985;5:2539–2544.Google Scholar
  60. 60.
    Lane RF, Blaha CD, Rivet JM: Selective inhibition of mesolimbic dopamine release following chronic administration of clozapine: involvement of alphar noradrenergic receptor demonstrated by in vivo voltammetry. Brain Res 1988;460:398–401.PubMedGoogle Scholar
  61. 61.
    Meltzer HY, Daniels S, Fang VS: Clozapine increases rat serum prolactin levels. Life Sci 1975;17:339–342.PubMedGoogle Scholar
  62. 62.
    Gudelsky GA, Berry SA, Meltzer HY: Neurotensin activates tuberoinfundibular dopamine neurons and increases serum corticosterone concentrations. Neuroendocrinology 1989;49:604–609.PubMedGoogle Scholar
  63. 63.
    Gudelsky GA, Meltzer HY: Activation of tuberoinfundibular dopamine neurons following the acute administration of atypical antipsychotics. Neuropsychopharmacology 1989;2:45–51.PubMedGoogle Scholar
  64. 64.
    Gudelsky GA, Nash JF, Koenig JI, et al: Neuroendocrine effects of typical and atypical antipsychotics in the rat. Psychopharmacol Bull 1987;23:483–486.Google Scholar
  65. 65.
    Kabzinski AM, Szewczak MR, Cornfeldt ML, et al: Differential effects of dopamine agonists and antagonists on the spontaneous electrical activity of A9 and A10 dopamine neurons. Neurosci Abstr 1987;13:908.Google Scholar
  66. 66.
    Esposito E, Bunney BS: Effect of acute and chronic treatment with SCH 23390 on the spontaneous activity of midbrain dopamine neurons. Neurosci Abs 1988;14:931.Google Scholar
  67. 67.
    Goldstein JM, Litwin LC: Spontaneous activity of A9 and A10 dopamine neurons after acute and chronic administration of the selective dopamine D-1 receptor antagonist SCH 23390. Eur J Pharmacol 1988;155:175–180.PubMedGoogle Scholar
  68. 68.
    Andersen PH, Nielsen EB, Gronvald FC, et al: Some atypical neuroleptics inhibit [3-H]SCH-23390 binding in vivo. Eur J Pharmacol 1986;120:143–144.PubMedGoogle Scholar
  69. 69.
    Andersen PH, Braestrup C: Evidence for different states of the dopamine D- 1 receptor: clozapine and fluperlapine may preferentially label an adenylate cyclase-coupled state of the D-l receptor. J. Neurochemistry 1986;47:1830–1831.Google Scholar
  70. 70.
    Chipkin RE, Latranyi MB: Similarity of clozapine and SCH 23390 in reserpinized rats suggest a common mechanism of action. Eur J Pharmacol 1987;136:371–375.PubMedGoogle Scholar
  71. 71.
    Altar CA, Boyar WC, Wasley A, et al: Dopamine neurochemical profile of atypical antipsychotics resembles that of D-l antagonists. Naunyn-Schmie-deberg’s Arch Pharmacol 1988;338:162–168.Google Scholar
  72. 72.
    Maj J, Sowinska H, Boran L, et al: The central action of clozapine. Pol J Pharmacol Pharm 1974;26:425–435.PubMedGoogle Scholar
  73. 73.
    Ackenheil M, Beckmann H, Greil W, et al: Antipsychotic efficacy of clozapine in correlation to changes in catecholamine metabolism in man. Adv Biochem Psychopharm 1974;9:647–658.Google Scholar
  74. 74.
    Ruch W, Asper H, Btirki HR: Effect of clozapine on the metabolism of serotonin in rat brain. Psychopharmacologia (Berl) 1976;46:103–109.Google Scholar
  75. 75.
    Stralendorff B, Ackenheil M, Zimmerman J: Akute und chronishe werkung von clozapine, haloperidol und sulpirid auf den stoffwechsel giogener amine in rattenhirn. Arzneim Forsch 1976;26:1096–1098.Google Scholar
  76. 76.
    Banki CM: Alterations of cerebrospinal fluid 5-hydroxyindoleacetic acid, and total blood serotonin content during clozapine treatment. Psychopharmacology 1978;56:195–198.PubMedGoogle Scholar
  77. 77.
    Gerlach J, Thorsen K, Fog R: Extrapyramidal reactions and amine metabolites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenic patient. Psychopharmacologica (Berl) 1975;40:341–350.Google Scholar
  78. 78.
    Enjalbert A, Hamon M, Bourgoin S, et al: Postsynaptic serotonin-sensitive adenylate cyclase in the central nervous system. II. Comparison with dopamine- and isoproterenol-sensitive adenylate cyclases in rat brain. Mol Pharmacol 1978;14:11–23.Google Scholar
  79. 79.
    Green JP, Maayani S: Nomenclature, classification and notation of receptors: 5-hydroxytryptamine receptors and binding sties as examples, in Black JW, Jenkinson DH, Gerskowitch VP (eds): Perspective on Receptor Classification. New York, Alan R. Liss Inc., 1987; pp 237–267.Google Scholar
  80. 80.
    Conn PJ, Sanders-Bush E: Central serotonin receptors: effector symptoms, physiological roles and regulation. Psychopharmacology 1987;92: 267–277.PubMedGoogle Scholar
  81. 81.
    Devivo M, Maayani S: Characterization of the 5-hydroxytryptamine receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes. J Pharmacol Exp Ther 1986; 238:248–253.Google Scholar
  82. 82.
    Sulpizio A, Fowler FJ, Macko E: Antagonism of fenfluramine-induced hyperthermia: a measure of central serotonin inhibition. Life Sci 1978;22:1439–1446.PubMedGoogle Scholar
  83. 83.
    Fjalland B: Neuroleptic influence on hyperthermia induced by 5-hydroxy-tryptophan and p-methoxyamphetamine in MAOI-pretreated rabbits. Psy-chopharmacology 1979;63:113–117.Google Scholar
  84. 84.
    Maj J, Baran L, Bigajska BK, et al: The influence of neuroleptics on the behavioral effect of 5-hydroxytryptophan. Pol J Pharmacol Pharm 1978; 30:431–440.PubMedGoogle Scholar
  85. 85.
    Lai H, Carino MA, Horita A: Antiserotonin properties of neuroleptic drug, in HI Yamamura, RW Olsen, E Usdin (eds): Psychopharmacology and Biochemistry or Neurotransmitter Receptor. New York, Elsevier-North Hol¬land, 1980; pp 347–353.Google Scholar
  86. 86.
    Fink H, Morgenstern R, Oelssner W: Clozapine—a serotonin antagonist? Pharmacology Biochem Behavior 1984;20:513–517.Google Scholar
  87. 87.
    Friedman RL, Sanders-Bush E, Barrett RL: Clozapine blocks descriptive and discriminative stimulus effects of quipazine. Eur J Pharmacol 1985;106:191–193.Google Scholar
  88. 88.
    Nash JF, Meltzer HY, Gudelsky GA: Antagonism of serotonin receptor mediacted neuroendocrine and temperature responses by atypical neuroleptics in the rat. Eur J Pharmacol 1988;151:463–469.PubMedGoogle Scholar
  89. 89.
    Rasmussen K, Aghajanian GK: Potency of antipsychotics in reversing the effects of a hallucinogenic drug on locus coeruleus neurons correlates with 5-HT2 binding affinity. Neuropsychopharmacology 1988;1:101–107.PubMedGoogle Scholar
  90. 90.
    Waldmeier PC, Delini-Atula AA: Serotonin-dopamine interactions in the ni- grostriatal system. Eur J Pharmacol 1979;55:363–373.PubMedGoogle Scholar
  91. 91.
    Altar CA, Wasley AM, Neale RF, et al: Typical and atypical antipsychotic occupancy of D2 and S2 receptors: an autoradiographic analysis in rat brain. Brain Res Bull 1986;16:517–525.PubMedGoogle Scholar
  92. 92.
    Reynolds GP, Garrett NJ, Rupniak N, et al: Chronic clozapine treatment of rats downregulates cortical 5-HT2 receptors. Eur J Pharmacol 1983;89:325–326.PubMedGoogle Scholar
  93. 93.
    Lee T, Tang SW: Loxapine and clozapine decrease serotonin (S2) but do not elevate dopamine (D2 receptor numbers in the rat brain). Psychiatry Res 1984;12:277–285.PubMedGoogle Scholar
  94. 94.
    Matsubara S, Meltzer HY: Acute effects of neuroleptics on 5-HT2 receptor density in rat cerebral cortex. Life Science, in press.Google Scholar
  95. 95.
    Moret C: Pharmacology of the serotonin autoreceptor, in AR Green (ed): Neuropharmacology of Serotonin. Oxford, Oxford Press, 1985, pp 21–49.Google Scholar
  96. 96.
    Gothert M: Role of autoreceptors in the function of the peripheral and central nervous system. Drug Res 1985;35:1909–1916.Google Scholar
  97. 97.
    Hetey L, Drescher K, Oelssner W: Different influence of antipsychotics and serotonin antagonists on presynaptic receptors modulating the synaptosomal release of dopamine and serotonin. Wiss Z Humboldt-Univ Berl 1982; 31:487–489.Google Scholar
  98. 98.
    Drescher K, Hetey L: Influence of antipsychotics and serotonin antagonists on presynaptic receptors modulating the release of serotonin in synapto-somes of the nucleus accumbens of rats. Neuropharmacology 1988;27:31–36.PubMedGoogle Scholar
  99. 99.
    Bannon MJ, Roth RH: Pharmacology of mesocortical dopamine neurons. Pharmacol Res 1983;35:53–68.Google Scholar
  100. 100.
    Carter CJ, Pycock CJ: Behavioral and biochemical effects of dopamine and noradrenaline depletion within the medial prefrontal cortex of the rat. Brain Res 1980;192:163–176.PubMedGoogle Scholar
  101. 101.
    Scatton B, Worms P, Lloyd KG, et al: Cortical modulation of striatal function. Brain Res 1982;232:331–343.PubMedGoogle Scholar
  102. 102.
    Pycock CJ, Carter CJ, Kerwin RW: Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on neurotransmitter systems in subcortical sites in the rat. J Neurochem 1980;34:91–99.PubMedGoogle Scholar
  103. 103.
    Pycock CJ, Kerwin RW, Carter CJ: Effects of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature (Lomd) 1980;286:74–77.Google Scholar
  104. 104.
    Scatton B: Effect of repeated treatment with neuroleptics on dopamine metabolism in cell bodies and terminals in dopaminergic systems in the rat brain, in Cattabeni F, Racagni G, Spano PF, Costa E (eds): Advances in Biochemical Psychopharmacology. New York, Raven Press, 1980, pp 31–36.Google Scholar
  105. 105.
    Blanc G, Herve D, Simon H, et al: Response to stress of mesocorticofrontal dopaminergic neurons in rats after long-term isolation. Nature 1980;284:265–267.PubMedGoogle Scholar
  106. 106.
    Meltzer HY: Biochemical studies in schizophrenia, in L Bellak (ed): Disorders of the Schizophrenic Syndrome. New York, Basic Books, Inc., 1979, pp 45–149.Google Scholar
  107. 107.
    Meltzer HY: Dopamine and negative symptoms in schizophrenia: critique of the type I-type II hypothesis, in M Alpert (ed): Controversies in Schizophrenia: Changes and Constancies. New York, Guilford Press, 1985, pp 110–136.Google Scholar
  108. 108.
    Mackay AVP: Positive and negative schizophrenic symptoms and the role of dopamine. Br J Psychiatry 1980;137:379–383.PubMedGoogle Scholar
  109. 109.
    Costall B, Kelly DM, Naylor RJ: Nomifensine: a potent dopaminergic agonist of antiparkinson potential. Psychopharmacol (Berl) 1975;41:153–164.Google Scholar
  110. 110.
    Sanberg PR, Bunsey MD Giordano M, et al: The catalepsy test: its ups and downs. Behavioral Neurosci 1988;102:748–759.Google Scholar
  111. 111.
    Nicolaou NM, Garcia-Munoz M, Arbuthrott GW, et al: Interactions between serotonergic and dopaminergic systems in rat brain demonstrated by small unilateral lesions of the raphe nuclei. Eur J Pharmacol 1979;57:295–305.PubMedGoogle Scholar
  112. 112.
    Herve D, Simon H, Blanc G, et al: Increased utilization of dopamine in the nucleus accumbens but not in the cerebral cortex after dorsal raphe lesion in the rat. Neurosci Lett 1979;75:127–133.Google Scholar
  113. 113.
    Herve D, Simon H, Blanc G, et al: Opposite changes in dopamine utilization in the nucleus accumbens and the frontal cortex after electrolytic lesion of the median raphe in the rat. Brain Res 1981;216:422–428.PubMedGoogle Scholar
  114. 114.
    Lisoprawski A, Herve D, Blanc G, et al: Selective activation of the mesocortical frontal dopaminergic neurons induced by lesion of the habenula in the rat. Brain Res 1980;183:229–234.PubMedGoogle Scholar
  115. 115.
    Gallager DW, Aghaganian GK: Effect of antipsychotic drugs on the firing of dorsal raphe cells. I. Role of adrenergic system. Eur J Pharmacol 1976;39:341–355.PubMedGoogle Scholar
  116. 116.
    Stahl SM, Wets K: Indoleamines and schizophrenia, in Henn FA, DeLisi LE (eds): Handbook of Schizophrenia. Elsevier, Elsevier Science Publishing BV 1987, pp 257–296.Google Scholar
  117. 117.
    Bleich A, Brown S, Kahn R, et al: The role of serotonin in schizophrenia. Schiz Bull 1988;14:297.Google Scholar
  118. 118.
    Racagni G, Cheney DL, Trabucchi M, et al: In vivo actions of clozapine and haloperidol on the turnover rate of acetylcholine in rat striatum. J Pharmacol Exp Ther 1976;196:323–332.PubMedGoogle Scholar
  119. 119.
    Cohen BM, Lipinski JF: In vivo potencies of antipsychotic drugs in blocking alpha! noradrenergic and dopamine D-2 receptors: implications for drug mechanisms of action. Life Sci 1986;39:2571–2580.PubMedGoogle Scholar
  120. 120.
    Gross G, Schumann HJ: Effect of long-term treatment with atypical neuroleptic drugs on beta adrenoceptor binding in rat cerebral cortex and myocardium. Naunyn-Schmiedeberg s Arch Pharmacol 1982;321:271–275.Google Scholar
  121. 121.
    Maggi A, Cattebeni F, Bruno F, et al: Haloperidol and clozapine: specificity of action on GABA in the nigrostria system. Brain Res 1977;133:382–385.PubMedGoogle Scholar
  122. 122.
    Schmidt WJ: Intrastriatal injection of DL-2-amino-5-phosphonovaleric acid (AP-5) induces sniffing stereotypy that is antagonized by haloperidol and clozapine. Psychopharmacology 1986;90:123–130.PubMedGoogle Scholar
  123. 123.
    Kilts CD, Anderson CM, Bissette G, et al: Differential effects of antipsychotic drugs on the neurotensin concentration of discrete rat brain nuclei. Biochem Pharmacol 1988;37:1547–1554.PubMedGoogle Scholar

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© Springer-Verlag New York Inc. 1990

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  • Herbert Y. Meltzer

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