, Volume 115, Issue 1–2, pp 147–156 | Cite as

Systemic administration of amperozide, a new atypical antipsychotic drug, preferentially increases dopamine release in the rat medial prefrontal cortex

  • G. G. Nomikos
  • M. Iurlo
  • J. L. Andersson
  • K. Kimura
  • T. H. Svensson
Original Investigations


The putative atypical antipsychotic drug amperozide (APZ) shows high affinity for serotonin 5-HT2 receptors but only low affinity for dopamine (DA) D2 receptors. By employing microdialysis, we examined the effects of APZ on extracellular concentrations of DA in the nucleus accumbens (NAC), the dorsolateral striatum (STR) and the medial prefrontal cortex (MPC) of awake rats. A 5.0 mg/kg (SC) dose of APZ failed to affect DA concentrations in the NAC, while it increased DA outflow in the STR (by 46%) and the MPC (by 207%). A higher dose of APZ (10 mg/kg, SC) enhanced dialysate DA from the NAC and the STR by 30%, and from the MPC by 326%. Similarly, clozapine (2.5 and 10 mg/kg, SC) produced a greater release of DA in the MPC (+ 127 and + 279%) than in the NAC (+ 52 and + 98%). The selective 5-HT2 receptor antagonist ritanserin (1.5 and 3.0 mg/kg, SC) also produced a slightly higher increase of DA output in the MPC (+ 25 and + 47%) compared with the NAC (+ 19 and + 21%). In contrast, the selective D2 receptor antagonist raclopride (0.5 and 2.0 mg/kg, SC) increased DA release in the NAC (+ 65 and + 119%) to a greater extent than in the MPC (+ 45 and + 67%). These data suggest that the 5-HT2 receptor antagonistic properties of APZ and clozapine may contribute to their preferential effects on DA transmission in the MPC. Infusion of low doses (1,10 µM, 40 min) of APZ through the probe in the DA terminal areas did not affect significantly DA outflow, while infusion of high doses (100, 1000 µM, 40 min) resulted in a more pronounced elevation of DA levels in the NAC (up to 961%) and the STR (up to 950%) than in the MPC (up to 316%). These findings indicate that the selective action of systemically administered APZ on DA in the MPC is most likely mediated at a level other than the terminal region. Taken together, the present results provide support for the notion that 5-HT2 receptor antagonism may be of considerable significance for the action of atypical antipsychotic drugs on mesolimbocortical dopaminergic neurotransmission.

Key words

Amperozide Microdialysis Prefrontal cortex Nucleus accumbens Clozapine Ritanserin Raclopride Antipsychotics 


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  1. Altar CA, Wasley AM, Neale RF, Stone GE (1986) Typical and atypical antipsychotic occupancy of D2 and S2 receptors: an autoradiographic analysis in rat brain. Brain Res Bull 16:517–525Google Scholar
  2. Andén NE, Stock G (1973) Effects of clozapine on the turnover of dopamine in the corpus striatum and in the limbic system. J Pharm Pharmacol 25:346–348Google Scholar
  3. Ashby CR, Wang RY (1990) Effects of antipsychotic drugs on 5-HT2 receptors in the medial prefrontal cortex: microiontophoretic studies. Brain Res 506:346–348Google Scholar
  4. Axelsson R, Nilsson A, Christensson E, Björk A (1991) Effects of amperozide in schizophrenia. Psychopharmacology 104:287–292Google Scholar
  5. Bannon MJ, Reinhard JF, Bunney EB, Roth RH (1982) Unique response to antipsychotic drugs is due to absence of terminal autoreceptors in mesocortical dopamine neurons. Nature 306:791–792Google Scholar
  6. Bartholini G (1976) Differential effect of neuroleptic drugs on dopamine turnover in the extrapyramidal and limbic systems. J Pharm Pharmacol 28:429–433Google Scholar
  7. Berman KF, Weinberger DR (1990) Prefrontal dopamine and defect symptoms in schizophrenia. In: Greden JF, Tandon R (eds) Negative schizophrenic symptoms: pathophysiology and clinical implications (Progress in Psychiatry Series vol 28). American Psychiatric Press, Washington, DC, London, England, pp 81–95Google Scholar
  8. Björk A, Bergman I, Gustavsson G (1992) Amperozide in the treatment of schizophrenic patients. A preliminary report. In: Meltzer HY (ed) Novel antipsychotic drugs. Raven, New York, pp 47–57Google Scholar
  9. Carlsson M, Carlsson A (1989) The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice. J Neural Transm 75:221–226Google Scholar
  10. Carlsson M, Carlsson A (1990) Schizophrenia: a subcortical neurotransmitter imbalance syndrome? Schizophr Bull 16:425–432Google Scholar
  11. 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 3:1607–1619Google Scholar
  12. Chiodo LA, Bannon MJ, Grace AA, Roth RH, Bunney BS (1984) Evidence for the absence of impulse regulating somatodendritic and synthesis-modulating nerve terminal autoreceptors on subpopulations of mesocortical dopamine neurons. Neuroscience 12:1–16Google Scholar
  13. Christensson EG (1992) Amperozide and some other atypical compounds with antipsychotic effect. In: Meltzer HY (ed) Novel antipsychotic drugs. Raven, New York, pp 19–32Google Scholar
  14. Claghorn J, Honigfeld G, Abuzzahab FS, Wans R, Steinbook R, Tuason V, Klerman G (1987) The risks and benefits of clozapine versus chlorpromazine. J Clin Psychopharmacol 7:377–384Google Scholar
  15. Cohen BM, Lipinski JF (1986) In vivo potencies of antipsychotic drugs in blocking alpha1 noradrenergic and dopamine D2 receptors: implications for drug mechanisms of action. Life Sci 39:2571–2580Google Scholar
  16. Coward DM (1992) General pharmacology of clozapine. Br J Psychiatry 160 [Suppl 17]:5–11Google Scholar
  17. Deutch AY, Roth RH (1990) The determinants of stress-induced activation of the prefrontal cortical dopamine system. In: Uylings HBM, Van Eden CG, De Bruin JPC, Corner MA, Feenstra MGP (eds) Progress in brain research (vol 7). Elsevier, Amsterdam, pp 367–403Google Scholar
  18. Deutch AY, Moghaddam B, Innis RB, Krystal JH, Aghajanian GK, Bunney BS, Charney DS (1991) Mechanisms of action of atypical antipsychotic drugs. Implications for novel therapeutic strategies for schizophrenia. Schizophr Res 4:121–156Google Scholar
  19. Devaud LL, Hollingsworth EB, Cooper BR (1992) Alterations in extracellular and tissue levels of biogenic amines in rat brain induced by the serotonin2 receptor antagonist, ritanserin. J Neurochem 59:1459–1466Google Scholar
  20. 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 130:374–382Google Scholar
  21. Egbe PC (1989) Locomotor effects of amperozide. Arzneimittelforschungh 39:1223–1224Google Scholar
  22. Einhorn LC, Johansen PA, White FJ (1988) Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area. J Neurosci 8:100–112Google Scholar
  23. Eriksson E, Christensson E (1990) The effect of amperozide on uptake and release of3H-dopamine in vitro from perfused rat striatal and limbic brain areas. Pharmacol Toxicol 66 [Suppl 1]:45–48Google Scholar
  24. Fink H, Morgenstern R, Oetssner W (1984) Clozapine — A serotonin antagonist? Pharmacol Biochem Behav 20:513–517Google Scholar
  25. Fischer-Cornelsson KA, Ferne UJ (1976) An example of european multicenter trials: multispectral analysis of clozapine. Psychopharmacol Bull 12:34–39Google Scholar
  26. Fitton A, Heel RC (1990) Clozapine. A review of its pharmacological properties, and therapeutic use in schizophrenia. Drugs 40 [5]:722–747Google Scholar
  27. Galloway MP, Wolf ME, Roth RH (1986) Regulation of dopamine synthesis in the medial prefrontal cortex is mediated by release modulating autoreceptors: studies in vivo. J Pharmacol Exp Ther 236:689–698Google Scholar
  28. Gelders YG (1989) Thymosthenic agents, a novel approach in the treatment of schizophrenia. Br J Psychiatry 155:33–36Google Scholar
  29. Gelders YG, VandenBussche G, Reyntjens A. Janssen P (1986) Serotonin-S2 receptor blockers in the treatment of chronic schizophrenia. Clin Neuropharmacol 9:327–327Google Scholar
  30. Grenhoff J, Tung C, Ugedo L, Svensson TH (1990) Effects of amperozide, a putative antipsychotic drug, on rat midrain dopamine neurons recorded in vivo. Pharmacol Toxicol 66 [Suppl 1]:29–33Google Scholar
  31. Gustafsson B, Christensson E (1990a) Amperozide — a new putatively antipsychotic drug with a limbic mode of action on dopamine mediated behavior. Pharmacol Toxicol 66 [Suppl 1]:12–17Google Scholar
  32. Gustafsson B, Christensson E (1990b) Amperozide and emotional behavior. Pharmacol Toxicol 66 [Suppl 1]:34–39Google Scholar
  33. Hadfield MG, Nugent EA (1983) Cocaine: comparative effect on dopamine uptake in extrapyramidal and limbic systems. Biochem Pharmacol 32:744–746Google Scholar
  34. Hand TH, Hu X-T, Wang RY (1987) Differential effects of acute clozapine and haloperidol on the activity of ventral tegmental (A10) and nigrostriatal (A9) dopamine neurons. Brain Res 415:257–269Google Scholar
  35. Haskins JT, Muth EA, Andree TH (1987) Biochemical and electrophysiological studies of the psychotropic compound, amperozide. Brain Res Bull 19:465–471Google Scholar
  36. Hervé D, Simon H, Blanc G, Lisoprawski A, Le Moal M, Glowinski J, Tassin JP (1979) Increased utilization of dopamine in the nucleus accumbens but not in the cerebral crotex after dorsal raphe lesion in the rat. Neurosci Lett 15:127–134Google Scholar
  37. Hervé D, Simon H, Blanc G, Le Moal M, Glowinski J, Tassin JP (1981) 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 216:422–428Google Scholar
  38. Hoffman DC (1992) Typical and atypical neuroleptics antagonize MK-801-induced locomotion and stereotypy in rats. J Neural Transm 89:1–10Google Scholar
  39. Hommer DW, Zahn TP, Pickar D, Van Kammen DP (1984) Prazosin, a specific alpha1-noradrenergic receptor antagonist has no effect on symptoms but increases autonomic arousal in schizophrenic patients. Psychiatry Res 11:193–204Google Scholar
  40. Ichikawa J, Meltzer HY (1992) Amperozide, a novel antipsychotic drug, inhibits the ability ofd-amphetamine to increase dopamine release in vivo in rat striatum and nucleus accumbens. J Neurochem 58:2285–2291Google Scholar
  41. Imperato A, Angelucci L (1989) The effects of clozapine and fluperlapine on the in vivo release and metabolism of dopamine in the striatum and in the prefrontal cortex of freely moving rats. Psychopharmacol Bull 25:383–389Google Scholar
  42. Imperato A, Di Chiara G (1985) Dopamine release and metabolism in awake rats after systemic neuroleptics as studied by transstriatal dialysis. J Neurosci 5:297–306Google Scholar
  43. Imperato A, Di Chiara G (1988) Effects of locally applied D-1 and D-2 receptor agonists and antagonists studied with brain dialysis. Eur J Pharmacol 156:385–393Google Scholar
  44. Ingvar DH (1987) Evidence for frontal/prefrontal cortical dysfunction in chronic schizophrenia: the phenomenon of hypofrontality reconsidered. In: Helmchen H, Henn FA (eds) Biological perspectives of schizophrenia. Wiley, New York, pp 201–211Google Scholar
  45. 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 100:774–778Google Scholar
  46. Janssen PAJ, Niemegeers CJE, Awouters F, Schellekens KHL, Megens AAHP, Meert TF (1988) Pharmacology of risperidone (R 64 766), a new antipsychotic drug with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 244:685–693Google Scholar
  47. Kalivas PW, Duffy P, Barrow J (1989) Regulation of the mesocorticolimbic dopamine system by glutamic acid receptor subtypes. J Pharmacol Exp Ther 251:378–387Google Scholar
  48. Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic. Arch Gen Psychiatry 45:789–796Google Scholar
  49. Kim JS, Kornhuber HH, Schmid-Burgk W, Holzmüller B (1980) Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neurosci Lett 20:379–382Google Scholar
  50. Kimura K, Nomikos GG, Svensson TH (1993) Effects of amperozide on psychostimulant-induced hyperlocomotion and dopamine release in the nucleus accumbens. Pharmacol Biochem Behav 44:27–36Google Scholar
  51. Köhler C, Hall H, Ögren S-O, Gawell L (1985) Specific in vivo and in vitro binding of3H-raclopride. Biochem Pharmacol 34:2251–2259Google Scholar
  52. Lane RF, Blaha CD, Rivet JM (1988) Selective inhibition of mesolimbic dopamine release following chronic administration of clozapine: involvement of α1-noradrenergic receptors demonstrated by in vivo voltammetry. Brain Res 460:398–401Google Scholar
  53. Leysen JE, Commeron W, Van Gompel P, Wynants J, Janssen PFM, Laduron PM (1985) Receptor-binding properties in vitro and in vivo of ritanserin. A very potent and long acting serotonin-S2 antagonist. Mol Pharmacol 27:600–611Google Scholar
  54. Mantz J, Godbout R, Tassin J-P, Glowinski J, Thierry A-M (1990) Inhibition of spontaneous and evoked unit activity in the rat medial prefrontal cortex by mesencephalic raphe nuclei. Brain Res 524:22–30Google Scholar
  55. Meltzer HY, Nash JF (1991) VII. Effects of antipsychotic drugs on serotonin receptors. Pharmacol Rev 43:587–604Google Scholar
  56. Meltzer HY, Matsubara S, Lee JC (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 251:238–246Google Scholar
  57. Meltzer HY, Zhang Y, Stockmeier CA (1992) Effects of amperozide on rat cortical 5-HT2 and striatal and limbic dopamine D2 receptor occupancy: implications for antipsychotic action. Eur J Pharmacol 216:67–71Google Scholar
  58. Moghaddam B, Bunney BS (1989) Differential effect of cocaine on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens: comparison to amphetamine. Synapse 4:156–161Google Scholar
  59. Moghaddam B, Bunney BS (1990a) Acute effects of typical and atypical antipsychotic drugs on the release of dopamine from prefrontal cortex, nucleus accumbens, and striatum of the rat: an in vivo microdialysis study. J Neurochem 54:1755–1760Google Scholar
  60. Moghaddam B, Bunney BS (1990b) Utilization of microdialysis for assessing the release of mesotelencephalic dopamine following clozapine and other antipsychotic drugs. Prog Neuropsychopharmacol Biol Psychiatry 14:S51-S57Google Scholar
  61. Murase S, Grenhoff J, Chouvet G, Gonon FG, Svensson TH (1993) Prefrontal cortex regulates burst firing and transmitter release in mesolimbic dopamine neurons studied in vivo. Neurosci Lett 155:53–56Google Scholar
  62. Nash JF, Meltzer HY, Gudelsky GA (1988) Antagonism of serotonin receptor-mediated neuroendocrine and temperature responses by atypical neuroleptics in the rat. Eur J Pharmacol 151:463–469Google Scholar
  63. Nomikos GG, Damsma G, Wenkstern D, Fibiger HC (1989) Acute effects of bupropion on extracellular dopamine concentrations in rat striatum and nucleus accumbens studied by in vivo microdialysis. Neuropsychopharmacology 2:273–281Google Scholar
  64. Nomikos GG, Damsma G, Wenkstern D, Fibiger HC (1990) In vivo characterization of locally applied dopamine uptake inhibitors by striatal microdialysis. Synapse 6:106–112Google Scholar
  65. Nomikos GG, Damsma G, Wenkstern D, Fibiger HC (1992) Effects of chronic bupropion on interstitial concentrations of dopamine in rat nucleus accumbens and striatum. Neuropsychopharmacology 7:7–14Google Scholar
  66. O'Connor WT, Drew KL, Ungerstedt U (1989) Differences in dopamine release and metabolism in rat striatal subregions following acute clozapine using in vivo microdialysis. Neurosci Lett 98:211–216Google Scholar
  67. Ögren SO, Hall H, Kohler C, Magnusson O, Sjöstrand SE (1986) The selective D2 receptor antagonist raclopride discriminates between dopamine-mediated motor functions. Psychopharmacology 90:287–294Google Scholar
  68. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, LondonGoogle Scholar
  69. Pazos A, Cortés R, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors. Brain Res 346:231–249Google Scholar
  70. Pellegrino LK, Pellegrino AA, Cushman AJ (1979) A stereotaxic atlas of the rat brain, Plenum, New YorkGoogle Scholar
  71. Peroutka SJ, Snyder SH (1980) Relationship of neuroleptic drug effects at brain dopamine, serotonin, α. adrenergic and histamine receptors to clinical potency. Am J Psychiatry 137:1518–1522Google Scholar
  72. Pettersson G, Johannessen K, Hulthe P, Engel JA (1990) Effect of amperozide on the synthesis and turnover of monoamines in rat brain. Pharmacol Toxicol 66 [Suppl 1]:40–44Google Scholar
  73. Robertson GS, Fibiger HC (1992) Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine. Neuroscience 46:315–328Google Scholar
  74. Ross SB (1978) The central stimulatory action of inhibitors of the dopamine uptake. Life Sci 24:159–168Google Scholar
  75. Santiago M, Westerink, BHC (1991) The regulation of dopamine release from nigrostriatal neurons in conscious rats: the role of somatodendritic autoreceptors. Eur J Pharmacol 204:79–85Google Scholar
  76. Schmidt WJ (1986) Intrastriatal injection of DL-2-amino-5-phosphonovaleric acid (AP-5) induces sniffing stereotypy that is antagonized by haloperidol and clozapine. Psychopharmacology 90:123–130Google Scholar
  77. Schotte A, de Bruyckere K, Janssen PFM, Leysen JL (1989) Receptor occupancy by ritanserin and risperidone measured using ex vivo autoradiography. Brain Res 500:295–301Google Scholar
  78. See RE, Sorg BA, Chapman MA, Kalivas PW (1991) in vivo assessment of release and metabolism of dopamine in the ventrolateral straitum of awake rats following administration of dopamine D1 and D2 receptor agonists and antagonists. Neuropharmacology 30:1269–1274Google Scholar
  79. Seeman P, Grigoriadis D (1987) Dopamine receptors in brain and periphery. Neurochem Int 10:1–25Google Scholar
  80. Sokoloff P, Giros B, Martres M-P, Bouthenet M-L, Schwartz J-C (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146–151Google Scholar
  81. Suaud-Chagny MF, Chergui K, Chouvet G, Gonon FG (1992) Relationship between dopamine release in the rat nucleus accumbens and the discharge activity of dopaminergic neurons during local in vivo application of amino acids in the ventral tegmental area. Neuroscience 49:63–72Google Scholar
  82. Svartengren J, Simonsson P (1990) Receptor binding properties of amperozide. Pharmacol Toxicol 66 [Suppl 1]:8–11Google Scholar
  83. Svensson TH, Tung C-S, Grenhoff J (1989) The 5-HT2 antagonist ritanserin blocks the effect of pre-frontal cortex inactivation on rat A10 dopamine neurons in vivo. Acta Physiol Scand 136:497–498Google Scholar
  84. Tiedtke PI, Bischoff C, Schmidt WJ (1990) MK-801-induced stereotypy and its antagonism by neuroleptic drugs. J Neural Transm 81:173–182Google Scholar
  85. Ugedo L, Grenhoff J, Svensson TH (1989) Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition. Psychopharmacology 98:45–50Google Scholar
  86. Van Tol HHM, Bunzow JR, Guan H-C, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–614Google Scholar
  87. Waters N, Pettersson G, Carlsson A, Svensson K (1989) The putatively antipsychotic agent amperozide produces behavioral stimulation in the rat. Naunyn Schmiedebergs Arch Pharmacol 340:161–169Google Scholar
  88. Weinberger DR (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660–669Google Scholar
  89. Westerink BHC, de Vries JB (1989) On the mechanism of neuroleptic induced increase in striatal dopamine release: brain dialysis provides direct evidence for mediation by autoreceptors localized on nerve terminals. Neurosci Lett 99:197–202Google Scholar
  90. White FJ, Wang RY (1983) Differential effect of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons. Science 221:1054–1055Google Scholar
  91. Wright IK, Garratt JC, Marsden CA (1990) Effects of a selective 5-HT2 agonist, DOI, on 5-HT neuronal firing in the dorsal raphe nucleus and 5-HT release and metabolism in the frontal cortex. Br J Pharmacol 99:221–222Google Scholar
  92. Yamamoto BK, Meltzer HY (1992) The effect of the atypical antipsychotic drug, amperozide, on carrier-mediated striatal dopamine release measured in vivo. J Pharmacol Exp Pharmacol 263:180–185Google Scholar
  93. 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 106:27–37Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • G. G. Nomikos
    • 1
  • M. Iurlo
    • 1
  • J. L. Andersson
    • 1
  • K. Kimura
    • 1
  • T. H. Svensson
    • 1
  1. 1.Department of PharmacologyKarolinska InstitutetStockholmSweden

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