Download PDF
Pharmacopsychiatry 2006; 39: 15-20
DOI: 10.1055/s-2006-931484
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

The Complexity of the Dopaminergic Synapses and their Modulation by Antipsychotics

K. Leuner1 , W. E. Müller1
  • 1Department of Pharmacology, Biocenter, Goethe University, Frankfurt, Germany
Further Information

Publication History

Publication Date:
01 March 2006 (online)

Also available at
    Permissions and Reprints

Since the mid of the 1960ies, striking similarities between the psychosis seen in subjects taking high doses of amphetamines and the symptoms of patients with paranoid schizophrenia have been noted and placed in the context of increased catecholaminergic neurotransmission as a fundamental cause underlying major symptoms of the disease. Subsequent studies emphasized the contribution of central dopaminergic mechanisms for at least several psychotic symptoms of schizophrenia. The most compelling pharmacological data to support the developing ”dopamine hypothesis of schizophrenia” originated from the clear relationship between antipsychotic drug efficacy and affinity for D2 - like dopamine receptors strongly indicating D2-antagonism as major if not exclusive mechanism of antipsychotic drug action. Accordingly, in this review we focus on the neuropharmacology of the dopaminergic system in our brain with special emphasis on the dopaminergic synapse.

References

  • 1 Abi-Dargham A, Laruelle M. Mechanisms of action of second generation antipsychotic drugs in schizophrenia: insights from brain imaging studies.  European Psychiatry. 2005;  20 15-27
    CrossrefPubMedGoogle Scholar
  • 2 Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles L S, Weiss R, Cooper T B, Mann J J, Van Heertum R L, Gorman J M, Laruelle M. Increased baseline occupancy of D-2 receptors by dopamine in schizophrenia.  Proceedings of the National Academy of Sciences of the United States of America. 2000;  97 8104-8109
    CrossrefPubMedGoogle Scholar
  • 3 Bonci A, Hopf F W. The dopamine D2 receptor: New surprises from an old friend.  Neuron. 2005;  47 335-338
    CrossrefPubMedGoogle Scholar
  • 4 Bristow L J, Kramer M S, Kulagowski J, Patel S, Ragan C I, Seabrook G R. Schizophrenia and L-745,870, a novel dopamine D4 receptor antagonist.  Trends Pharmacol Sci.. 1997;  18 186-188
    PubMedGoogle Scholar
  • 5 Capuano B, Crosby I T, Lloyd E J. Schizophrenia: genesis, receptorology and current therapeutics.  Curr.Med.Chem. 2002;  9 521-548
    PubMedGoogle Scholar
  • 6 Chang W H, Jaw S S, Tsay L. Chronic Haloperidol Treatment with Low-Doses May Enhance the Increase of Homovanillic-Acid in Rat-Brain.  European Journal of Pharmacology. 1989;  162 151-156
    CrossrefPubMedGoogle Scholar
  • 7 De Camilli P, Macconi D, Spada A. Dopamine inhibits adenylate cyclase in human prolactin-secreting pituitary adenomas.  Nature. 1979;  278 252-254
    PubMedGoogle Scholar
  • 8 Dresel S, Mager T, Rossmuller B, Meisenzahl E, Hahn K, Moller H J, Tatsch K. In vivo effects of olanzapine on striatal dopamine D-2/D-3 receptor binding in schizophrenic patients: an iodine-123 iodobenzamide single-photon emission tomography study.  European Journal of Nuclear Medicine. 1999;  26 862-868
    CrossrefPubMedGoogle Scholar
  • 9 Farde L, Nordstrom A L, Karlsson P, Halldin C, Sedvall G. Positron Emission Tomography Studies on Dopamine-Receptors in Schizophrenia.  Clinical Neuropharmacology. 1995;  18 S121-129
    PubMedGoogle Scholar
  • 10 Farde L, Nordstrom A L, Wiesel F A, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects.  Arch Gen Psychiatry. 1992;  49 538-544
    Google Scholar
  • 11 Goldman-Rakic P S, Castner S A, Svensson T H, Siever L J, Williams G V. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction.  Psychopharmacology (Berl). 2004;  174 3-16
    PubMedGoogle Scholar
  • 12 Grace A A, Bunney B S, Moore H, Todd C L. Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs.  Trends in Neurosciences. 1997;  20 31-37
    Google Scholar
  • 13 Gurevich E V, Bordelon Y, Shapiro R M, Arnold S E, Gur R E, Joyce J N. Mesolimbic dopamine D-3 receptors and use of antipsychotics in patients with schizophrenia - A postmortem study.  Archives of General Psychiatry. 1997;  54 225-232
    PubMedGoogle Scholar
  • 14 Huff R M. Signaling pathways modulated by dopamine receptors. 1997: 167-192
    Google Scholar
  • 15 Joyce J N, Milian M J. Dopamine D-3 receptor antagonists as therapeutic agents.  Drug Discovery Today. 2005;  10 917-925
    CrossrefPubMedGoogle Scholar
  • 16 Kapur S, Mamo D. Half a century of antipsychotics and still a central role for dopamine D2 receptors.  Prog Neuropsychopharmacol Biol Psychiatry. 2003;  27 1081-1090
    Google Scholar
  • 17 Miyamoto S, Duncan G E, Marx C E, Lieberman J A. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs.  Mol.Psychiatry. 2005;  10 79-104
    CrossrefPubMedGoogle Scholar
  • 18 Moller H J. Antipsychotic and antidepressive effects of second generation antipsychotics - Two different pharmacological mechanisms?.  European Archives of Psychiatry and Clinical Neuroscience. 2005;  255 190-201
    CrossrefPubMedGoogle Scholar
  • 19 Neve K A, Seamans J K, Trantham-Davidson H. Dopamine receptor signaling.  Journal of Receptors and Signal Transduction. 2004;  24 165-205
    CrossrefPubMedGoogle Scholar
  • 20 Nordstrom A L, Farde L, Eriksson L, Halldin C. No Elevated D-2 Dopamine-Receptors in Neuroleptic-Naive Schizophrenic-Patients Revealed by Positron Emission Tomography and [C-11] N-Methylspiperone.  Psychiatry Research-Neuroimaging. 1995;  61 67-83
    PubMedGoogle Scholar
  • 21 Nordstrom A L, Farde L, Wiesel F A, Forslund K, Pauli S, Halldin C, Uppfeldt G. Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients.  Biol.Psychiatry. 1993;  33 227-235
    CrossrefPubMedGoogle Scholar
  • 22 Okubo Y, Suhara T, Sudo Y, Toru M. Possible role of dopamine D1 receptors in schizophrenia.  Molecular Psychiatry. 1997;  2 291-292
    CrossrefPubMedGoogle Scholar
  • 23 Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O, Someya Y, Sassa T, Sudo Y, Matsushima E, Iyo M, Tateno Y, Toru M. Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET.  Nature. 1997;  385 634-636
    CrossrefPubMedGoogle Scholar
  • 24 Seeman P. Dopamine Receptor Sequences - Therapeutic Levels of Neuroleptics Occupy D2-Receptors, Clozapine Occupies D4.  Neuropsychopharmacology. 1992;  7 261-284
    PubMedGoogle Scholar
  • 25 Seeman P and Kapur S. Olanzapine Binding to Dopamine Receptors in Vitro and in Vivo. In Tran, PV et al., editors. Olanzapine (Zyprexa®): A novel antipsychotic. Philadelphia: Lippincott Williams & Wilkings;. 2000.: p. 3-24
    Google Scholar
  • 26 Seeman P, Kapur S. Schizophrenia: More dopamine, more D-2 receptors.  Proceedings of the National Academy of Sciences of the United States of America. 2000;  97 7673-7675
    CrossrefPubMedGoogle Scholar
  • 27 Seeman P, Lee T, Chauwong M, Wong K. Antipsychotic Drug Doses and Neuroleptic-Dopamine Receptors.  Nature. 1976;  261 717-719
    Google Scholar
  • 28 Seeman P, Weinshenker D, Quirion R, Srivastava I AK, Bhardwaj S K, Grandy D K, Premont R T, Sotnikova T D, Boksa P, El Ghundi M, O'Dowd B F, George S R, Perreault M L, Mannisto P T, Robinson S, Palmiter R D, Tallerico T. Dopamine supersensitivity correlates with D2(High) states, implying many paths to psychosis.  Proceedings of the National Academy of Sciences of the United States of America. 2005;  102 3513-3518
    CrossrefPubMedGoogle Scholar
  • 29 Stevens J R. Anatomy of Schizophrenia.  Archives of General Psychiatry. 1973;  29 177-189
    PubMedGoogle Scholar
  • 30 Strange P G. Antipsychotic drugs: Importance of dopamine receptors for mechanisms of therapeutic actions and side effects.  Pharmacological Reviews. 2001;  53 119-133
    PubMedGoogle Scholar
  • 31 Tauscher J, Kufferle B, Asenbaum S, Tauscher-Wisniewski S, Kasper S. Striatal dopamine-2 receptor occupancy as measured with [I-123]iodobenzamide and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol.  Psychopharmacology. 2002;  162 42-49
    CrossrefPubMedGoogle Scholar
  • 32 Truffinet P, Tamminga C A, Fabre L F, Meltzer H Y, Riviere M E, Papillon-Downey C. Placebo-controlled study of the D4/5-HT2A antagonist fananserin in the treatment of schizophrenia.  Am. J.Psychiatry. 1999;  156 419-425
    PubMedGoogle Scholar
  • 33 Wadenberg M LG, Jones C, Kapur S, Soliman A, Vaccarino F, Wilson A. Quantitative relationship between in vivo dopamine D2 receptor occupancy and catalepsy in rats.  International Journal of Psychology. 2000;  35 421
    PubMedGoogle Scholar
  • 34 Wong D F, Young D, Wilson P D, Meltzer C C, Gjedde A. Quantification of neuroreceptors in the living human brain. D-2-like dopamine receptors: Theory, validation, and changes during normal aging.  Journal of Cerebral Blood Flow and Metabolism. 1997;  17 316-330
    PubMedGoogle Scholar

Prof. Dr. W. E. Müller

Department of Pharmacology

Biocenter

Goethe University

Marie-Curie-Str. 9

D-60439 Frankfurt

Germany

Phone: +49 69 79829373

Fax: +49 69 79829374

Email: PharmacolNat@em.uni-frankfurt.de

      >