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Dopamine Receptors and Antipsychotic Drug Response

Published online by Cambridge University Press:  06 August 2018

Roger K. Sunahara ,
Philip Seeman ,
Hubert H. M. Van Tol  and
Hyman B. Niznik
Roger K. Sunahara*
Affiliation:
Departments of Psychiatry and Pharmacology, University of Toronto, and Laboratory of Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto
Philip Seeman
Affiliation:
Departments of Psychiatry and Pharmacology, University of Toronto, and Laboratory of Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto
Hubert H. M. Van Tol
Affiliation:
Departments of Psychiatry and Pharmacology, University of Toronto, and Laboratory of Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto
Hyman B. Niznik
Affiliation:
Departments of Psychiatry and Pharmacology, University of Toronto, and Laboratory of Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto
*
∗Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
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Abstract

Dopamine receptors have been divided into two major types – D1 and D2 – based primarily on pharmacological and biochemical criteria. Recent advances in the molecular biology of the dopamine receptor system have allowed the identification and characterisation of at least five distinct neuronal dopamine receptor genes (D1 to D5). These genes encode dopamine receptors belonging to the D1 receptor family, termed D1 and D5, and three D2-like receptors, termed D2, D3 and D4. These receptors are distinguished on the basis of their primary structure, chromosomal location, mRNA size and tissue distribution, and biochemical and pharmacological differences. Although individually these receptor subtypes may not be directly and exclusively involved in the maintenance or expression of schizophrenia, alterations of any of the receptors may contribute to the perturbation or instability of dopaminergic homeostasis in the brain. What was once thought to be a simple two-receptor system seems to have emerged as an intricate and interactive entity. This review summarises what is currently understood about dopamine receptors, their role in antipsychotic drug action, and their association with psychosis.

Type
Research Article
Information
The British Journal of Psychiatry , Volume 163 , Issue S22: The Psychopharmacology of Schizophrenia , December 1993 , pp. 31 - 38
Copyright
Copyright © 1993 The Royal College of Psychiatrists 

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References

Alberts, P. R., Neve, K. A., Bunzow, J. R., et al (1990) Coupling of a cloned rat dopamine-D2 receptor inhibition of adenylate cyclase and prolactin release. Journal of Biological Chemistry, 265, 2098–2104.Google Scholar
Andersen, P. H., Gingrich, J. A., Bates, M. D., et al (1990) Dopamine receptor subtypes: beyond the D1/D2 classification. Trends in Pharmacological Sciences, 11, 231–236.Google Scholar
Andreasen, N. C. (1988) Brain imaging: applications in psychiatry. Science, 239, 1381–1388.Google Scholar
Arnt, J. (1985) Differential effects of dopamine D-1 and D-2 agonists and antagonists in 6-hydroxy-dopamine-lesioned rats. In Dyskinesia – Research and Treatment (Psychopharmacology suppl. 2) (eds Casey, D., Chase, T., Cristensen, V., et al), pp. 60–61. Berlin: Springer-Verlag.Google Scholar
Autelitano, D. J., Snyder, L., Sealfon, S. C., et al (1989) Dopamine D2-receptor mRNA is differentially regulated by dopaminergic agents in rat anterior and neurointermediate pituitary. Molecular and Cellular Endocrinology, 67, 101–105.CrossRefGoogle ScholarPubMed
Barone, P., Davis, T. A., Braun, A. R., et al (1986) Dopaminergic mechanisms and motor function: characterization of D-1 and D-2 dopamine receptor interactions. European Journal of Pharmacology, 123, 109–114.Google Scholar
Bertorello, A. M., Hopfield, J. E., Aperia, A., et al (1990) Inhibition by dopamine of Na + K ATPase activity through D1 and D2 dopamine receptor synergism. Nature, 347, 386–388.Google Scholar
Blum, K., Noble, E. P., Sheridan, P. J., et al (1990) Allelic association of the human dopamine D2 receptor gene in alcoholism. Journal of the American Medical Association, 263, 2055–2060.Google Scholar
Blum, K., Noble, E. P., Sheridan, P. J., et al (1991) Association of the A1 allele of the D2 dopamine receptor gene with severe alcoholism. Alcohol, 8, 409–416.Google Scholar
Bunzow, J. R., Van Tol, H. H. M., Grandy, D. K., et al (1988) Cloning and expression of a rat D2 dopamine receptor cDNA. Nature, 336, 783–787.Google Scholar
Chio, C. L., Hess, G. F., Graham, R. S., et al (1990) A second molecular form of D2 receptor in rat and bovine caudate nucleus. Nature, 343, 266–269.CrossRefGoogle ScholarPubMed
Chipkin, R. E., Iorio, L. C., Coffin, V. L., et al (1988) Pharmacological profile of SCH 39166: a D1 selective benzonaphthazepine with potential antipsychotic activity. Journal of Pharmacology and Experimental Therapeutics, 247, 1093.Google Scholar
Civelli, O., Bunzow, J. R., Grandy, D. K., et al (1991) Molecular biology of the dopamine receptors. European Journal of Pharmacology, 207, 277–286.Google Scholar
Clair, D. St, Blackwood, D., Muir, W., et al (1989) No linkage of chromosome 5q11-q-13 markers to schizophrenia in Scottish families. Nature, 339, 305–309.CrossRefGoogle Scholar
Clark, D. & White, F. J. (1987) D1 dopamine receptor – the search for a function. Synapse, 1, 347–388.Google Scholar
Comings, D. E., Comings, B. G., Muhleman, D., et al (1991) The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. Journal of the American Medical Association, 266, 1793–1800.Google Scholar
Dal Toso, R., Sommer, B., Ewert, M., et al (1989) The dopamine D2 receptor: two molecular forms generated by alternative splicing. European Molecular Biology Organization Journal, 8, 4025–4034.Google Scholar
Dearry, A. G., Gingrich, J. A., Falardeau, P., et al (1990) Molecular cloning and expression of the gene for a human D1 dopamine receptor. Nature, 347, 72–76.Google Scholar
Detera-Wadleigh, D. D. D., Goldin, L. R., Sherrington, R., et al (1989) Exclusion of linkage to 5q11–13 in families with schizophrenia and other psychiatric disorders. Nature, 340, 391–393.Google Scholar
Deutch, A. Y., Moghaddam, B., Innis, R., et al (1991) Mechanisms of action of atypical antipsychotic drugs: implications for novel therapeutic strategies for schizophrenia. Schizophrenia Research, 4, 121–156.Google Scholar
Dohlman, H. G., Thorner, J., Caron, M. G., et al (1991) Model systems for the study of seven transmembrane segment receptors. Annual Review of Biochemistry, 60, 653–688.Google Scholar
Egeland, J. A., Gerhardt, D. S., Pauls, D., et al (1987) Bipolar affective disorders linked to DNA markers on chromosome 11. Nature, 325, 393–399.CrossRefGoogle ScholarPubMed
Eubanks, J. H., Altherr, M., Wagner-McPherson, C., et al (1991) Localization of the D5 dopamine receptor gene to human chromosome 4p15.5–p15.3 centromeric to the Huntington's disease locus. Genomics, 12, 510–516.CrossRefGoogle Scholar
Farde, L., Wiesel, F. A., Stone-Elander, S., et al (1990) D2 dopamine receptors in neuroleptic-naïve schizophrenic patients: a positron emission tomography study with [11C]raclopride. Archives of General Psychiatry, 45, 213–219.CrossRefGoogle Scholar
Felder, C. C., Jose, P. A. & Axelrod, J. (1989a) The dopamine-1-agonist, SKF82526, stimulates phospholipase-C activity independent of adenylate cyclase. Journal of Pharmacology and Experimental Therapeutics, 248, 171–175.Google ScholarPubMed
Felder, C. C., Blecher, M. & Jose, P. A. (1989b) Dopamine-D1-mediated stimulation of phospholipase C activity in rat cortical membranes. Journal of Biological Chemistry, 264, 8739–8745.Google Scholar
Fremeau, R. T., Duncan, G. E., Fornaretto, M. G., et al (1991) Localization of D1 dopamine receptor mRNA in brain supports a role in cognitive, affective and neuroendocrine aspects of dopaminergic neurotransmission. Proceedings of the National Academy of Science, 88, 3772–3776.Google Scholar
Gelernter, J., Kennedy, J. L., Van Tol, H. H. M., et al (1992) The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS. Genomics, 13, 208–210.CrossRefGoogle ScholarPubMed
Gelernter, J., Kennedy, J. L., Grandy, D., et al (1993) Exclusion of close linkage of Tourette's syndrome to D1 dopamine receptor. American Journal of Psychiatry, 150, 449–453.Google Scholar
Giros, B., Sokoloff, P., Martres, M. P., et al (1989) Alternative splicing directs the expression of two D2 dopamine receptor isoforms. Nature, 342, 923–926.Google Scholar
Giros, B., Martres, M. P., Pilon, C., et al (1991) Shorter variants of the D3 dopamine receptor produced through various patterns of alternative splicing. Biochemical and Biophysical Research Communications, 176, 1584–1592.Google Scholar
Grandy, D. K., Marchionni, M. A., Makam, H., et al (1989a) The human dopamine D2 receptor gene is located on chromosome 11 at q22–q23 and identified a TaqI RFLP. American Journal of Human Genetics, 45, 778–785.Google ScholarPubMed
Grandy, D. K., Marchionni, M. A., Makam, H., et al (1989b) Cloning of the cDNA and gene for a human D2 dopamine receptor. Proceedings of the National Academy of Science, 86, 9762–9766.Google Scholar
Grandy, D. K., Zhang, Y., Bouvier, C., et al (1991) Multiple human D5 dopamine receptor genes: a functional receptor and two pseudogenes. Proceedings of the National Academy of Science, 88, 9175–9179.Google Scholar
Joyce, J. & Marshall, L. (1987) Quantitative autoradiography of dopamine D2 sites in rat caudate and putamen: localization to intrinsic neurons and not to neocortex afferents. Neuroscience, 20, 773.CrossRefGoogle ScholarPubMed
Kebabian, J. W. & Calne, D. B. (1979) Multiple receptors for dopamine. Nature, 277, 93–96.Google Scholar
Kennedy, J. L., Giuffra, L. A., Moises, H. W., et al (1988) Evidence against linkage of schizophrenia to markers on chromosome 5 in a northern Swedish kindred. Nature, 336, 167–170.Google Scholar
Kennedy, J. L., Sidenberg, D. G., Van Tol, H. H. M., et al (1991) A HincII RFLP in the human D4 dopamine receptor locus (DRD4). Nucleic Acid Research, 19, 5801.Google Scholar
Mahan, L. C., Burch, R. M., Monsma, R. C., et al (1990) Expression of striatal D1 dopamine receptors coupled to inositol phosphate production and Ca2+ mobilization in Xenopus oocytes. Proceedings of the National Academy of Science, 87, 2196–2200.Google ScholarPubMed
Mailman, R. B., Schulz, D. W., Kilts, C. D., et al (1986) Multiplicity of D1 dopamine receptors. In Neurobiology Control D1-Dopamine Receptors (eds Breese, G. R. & Creese, I.), pp. 53–72. New York: Plenum Press.Google Scholar
Mansour, A., Meader-Woodruff, J. H., Zhou, Q. Y., et al (1991) A comparison of D1 receptor binding and mRNA in rat brain using receptor autoradiographic and in situ hybridization techniques. Neuroscience, 45, 359–371.Google Scholar
McHugh, D. & Coffin, V. (1991) The reversal of extrapyramidal side effects with SCH-39166, a dopamine D1 receptor antagonist. European Journal of Pharmacology, 202, 133–134.Google Scholar
Mengod, G., Vilaro, M. T., Niznik, H. B., et al (1991) Visualization of a dopamine D1 receptor mRNA in human and rat brain. Molecular Brain Research, 10, 185–191.Google Scholar
Moises, H. W., Gelernter, J., Guiffra, L. A., et al (1991) No linkage between D2 dopamine receptor gene region and schizophrenia. Archives of General Psychiatry, 48, 643–647.Google Scholar
Monsma, F. J., Mahan, L. C., McVittie, L. D., et al (1990) Molecular cloning and expression of a D1 dopamine receptor linked to adenylate cyclase. Proceedings of the National Academy of Science, 87, 6723–6727.Google Scholar
Nguyen, T., Jin, H., Taruscio, D., et al (1991a) Dopamine D5 receptor human pseudogenes. Gene, 109, 211–218.Google Scholar
Nguyen, T., Sunahara, R., Marches, A., et al (19916) Transcription of a human dopamine D5 pseudogene. Biophysical and Biochemical Research Communications, 181, 16–21.Google Scholar
Niznik, H. B. (1987) Dopamine receptors: molecular structure and function. Molecular and Cellular Endocrinology, 54, 1–22.Google Scholar
Niznik, H. B., Fogel, E. L., Chen, C. J., et al (1988) Dopamine D1 receptors of the calf parathyroid gland: identification and characterization. Molecular Pharmacology, 34, 29–36.Google Scholar
Niznik, H. B. & Jarvie, K. R. (1989) Dopamine receptors. In Receptor Pharmacology and Function (eds Williams, M., Glennon, R. A. & Timmermans, P. B. M. W. M.), pp. 717–768. New York and Basel: Marcel Dekker.Google Scholar
Niznik, H. B. & Jarvie, K. R., Brown, E. M. (1989) Dopamine D1 receptors of the calf parathyroid gland: identification of a ligand binding subunit with lower apparent molecular weight but similar primary structure to neuronal D1 receptors. Biochemistry, 28, 6925–6930.Google Scholar
Niznik, H. B., O'Dowd, B. F., Sunahara, R. M., et al (1992) The dopamine D1 receptors. In Molecular Biology of Receptors that Couple to G-Proteins (ed. M. R. Brann), pp. 143–157. Birkhauser Boston Inc. (in press).CrossRefGoogle Scholar
O'Dowd, B. F., Lefkowitz, R. J. & Caron, M. G. (1989) Structure of the adrenergic and related receptors. Annual Review of Neuroscience, 12, 67–83.Google Scholar
Ohara, K., Ulpian, C., Seeman, P., et al (1993) Schizophrenia: dopamine D1 receptor sequence is normal, but reveals several DNA polymorphisms. Neuropsychopharmacology, 8, 131–135.Google Scholar
O'Malley, K., Mack, K., Gandelman, K., et al (1990) Organization and expression of the rat D2A receptor gene: identification of alternative transcripts and a variant donor splice site. Biochemistry, 29, 1367–1371.Google Scholar
Piomelli, D., Pilon, C., Giros, B., et al (1991) Dopamine activation of the arachidonate acid cascade as a basis of D1/D2 receptor synergism. Nature, 353, 164–167.Google Scholar
Polymeropoulos, M. H., Xiao, H. & Merril, C. R. (1991) The human D5 dopamine receptor (DRD5) maps to chromosome 4. Genomics, 11, 777.Google Scholar
Sandoz (1990) Clozaril: Summary of Preclinical and Clinical Data. Sandoz, Canada, Inc.Google Scholar
Sandrini, M., Benelli, A. & Baraldi, M. (1986) Regulatory effect of calcium on 3H-dopamine binding to guinea-pig heart membrane preparation. Pharmacological Research Communications, 17, 991–1003.Google Scholar
Sarkar, G., Kapelner, S., Grandy, D. K., et al (1991) Direct sequencing of the dopamine D2 receptor in schizophrenics reveals three polymorphisms but no structural change in the receptor. Genomics, 11, 8–14.Google Scholar
Seeman, P. (1980) Dopamine receptors. Pharmacology Review, 32, 229–313.Google Scholar
Seeman, P. (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse, 1, 133–152.Google Scholar
Seeman, P. (1990) Atypical neuroleptics: role of multiple receptors, endogenous dopamine, and receptor linkage. Acta Psychiatrica Scandinavica, 82 (suppl. 358), 14–20.Google Scholar
Seeman, P. (1992) Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4 . Neuro-psychopharmacology, 7, 261–284.Google Scholar
Seeman, P., Ulpian, C., Gergeron, C., et al (1984) Bimodal distribution of dopamine receptor densities in brains of schizophrenics. Science, 225, 728–731.CrossRefGoogle ScholarPubMed
Seeman, P. & Niznik, H. B. (1988) Dopamine D1 receptor pharmacology. Institute for Scientific Information Atlas of Science: Pharmacology, 2, 161–170.Google Scholar
Seeman, P. & Niznik, H. B., Guan, H.-C., et al (1989) Link between D1 and D2 dopamine receptors is reduced in schizophrenia and Huntington diseased brain. Proceedings of the National Academy of Science, 86, 10156–10160.Google Scholar
Seeman, P. & Niznik, H. B. (1990) Dopamine receptors and transporters in Parkinson's disease and schizophrenia. Federation of American Societies for Experimental Biology Journal, 4, 2737–2744.Google Scholar
Seeman, P. & Guan, H. C. (1990) Elevation of D2 dopamine receptors in schizophrenia are underestimated by radioactive raclopride. Archives of General Psychiatry, 47, 1170–1172.CrossRefGoogle ScholarPubMed
Selbie, L. A., Hayes, G. & Shine, J. (1989) The major dopamine D2 receptor: molecular analysis of the human D2A subtype. DNA, 8, 683–689.Google Scholar
Sherrington, R., Brynjolfsson, J., Pertursson, H., et al (1988) Localization of a susceptibility locus for schizophrenia on chromosome 5. Nature, 336, 164–167.Google Scholar
Sokoloff, P., Giros, B., Martes, M. P., et al (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature, 347, 146–151.Google Scholar
Stoof, J. C. & Kebabian, J. W. (1981) Opposing roles for D1 and D2 dopamine receptors in efflux of cyclic AMP from rat neostriatum. Nature, 294, 366–368.Google Scholar
Sunahara, R. K., Niznik, H. B., Weiner, D. M., et al (1990) Human dopamine D1 receptor encoded by an intronless gene on chromosome 5. Nature, 347, 80–83.Google Scholar
Sunahara, R. K., Guan, H.-C., O'Dowd, B. F., et al (1991) Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1 . Nature, 350, 614–619.Google Scholar
Tiberi, M., Jarvie, K. R., Silvia, C., et al (1991) Cloning molecular characterization and chromosomal assignment of a gene encoding a second D1 dopamine receptor subtype: differential expression pattern in rat brain compared with the D1a receptor. Proceedings of the National Academy of Science, 88, 7491–7495.CrossRefGoogle ScholarPubMed
Van Tol, H. H. M., Bunzow, J. R., Guan, H.-C., et al (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature, 350, 610–614.Google Scholar
Waddington, J. L. (1989) Functional interactions between D1 and D2 dopamine rceptor systems. Journal of Psychopharmacology, 3, 54–63.Google Scholar
Waddington, J. L. & O'Boyle, K. M. (1989) Drugs acting on dopamine receptors: a conceptual re-evaluation five years after the first selective D1 antagonist. Pharmacological Therapy, 43, 1–52.Google Scholar
Weiner, D. M., Levey, A. I., Sunahara, R. K., et al (1991) D1 and D2 dopamine receptor mRNA in rat brain. Proceedings of the National Academy of Science, 88, 1859–1863.Google Scholar
Weinshank, R. L., Adham, N., Macchi, M., et al (1991) Molecular cloning and characterization of a high affinity dopamine receptor and its pseudogenes. Journal of Biological Chemistry, 266, 22427–22435.Google Scholar
Wong, D. F., Wagner, H. N. Jr, Tune, L. E., et al (1986) Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science, 234, 1558–1563.CrossRefGoogle ScholarPubMed
Zhou, Q. Y., Grandy, D. K., Thambi, L., et al (1990) Cloning and the expression of human and rat D1 dopamine receptors. Nature, 347, 76–80.Google Scholar
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