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Neurochemical alterations in schizophrenia affecting the putative receptor targets of atypical antipsychotics

Focus on dopamine (D1, D3, D4) and 5-HT2a receptors

Published online by Cambridge University Press:  06 August 2018

P. J. Harrison
P. J. Harrison*
Affiliation:
University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX. Tel: 01865 226463; Fax: 01865251076; e-mail: paul.harrison@psychiatry.ox.ac.uk
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Extract

What mechanisms make an antipsychotic atypical? A common view is that the different therapeutic and side-effect profile of atypical compared to typical antipsychotics is due to their high affinity for specific dopamine and/or 5-HT (serotonin) receptors. Dopamine D4 and 5-HT2a receptors are particularly implicated, though many others have been proposed as well, including dopamine D1 and D3, 5-HT1a, 5-HT2c, 5-HT6, 5-HT7 and α2 adrenergic receptors (for review, see Deutch et al, 1991; Ashby & Wang, 1996; Kinon & Lieberman, 1996).

Type
Research Article
Information
The British Journal of Psychiatry , Volume 174 , Issue S38: New antipsychotics - preclinical and clinical comparisons , May 1999 , pp. 12 - 22
Copyright
Copyright © 1999 The Royal College of Psychiatrists 

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References

Andree, T. H., Mikuni, M., Tong, C. Y., et al (1986) Differential effect of subchronic treatment with various neuroleptic agents on serotonin2 receptors in rat cerebral cortex. Journal of Neurochemistry, 46, 191–197.Google Scholar
Arora, R. C. & Meltzer, H. Y. (1991) Serotonin2 (5-HT2) receptor binding in the frontal cortex of schizophrenic patients. Journal of Neural Transmission (General Section), 85, 19–29.CrossRefGoogle ScholarPubMed
Arranz, M., Collier, D., Sodhi, M., et al (1995) Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet, 346, 281–282.Google Scholar
Ashby, C. R. Jr & Wang, R. Y. (1996) Pharmacological actions of the atypical antipsychotic drug clozapine: A review. Synapse, 24, 349–354.3.0.CO;2-D>CrossRefGoogle ScholarPubMed
Bennett, J. P. Jr, Enna, S. J., Bylund, D. B., et al (1979) Neurotransmitter receptors in frontal cortex of schizophrenics. Archives of General Psychiatry, 36, 927–934.CrossRefGoogle ScholarPubMed
Berger, B., Gaspar, P. & Verney, C. (1991) Dopaminergic innervation of the cerebral cortex: unexpected differences between rodents and primates. Trends in Neurosciences, 14, 21–27.Google Scholar
Bergson, C., Mrzljak, L., Smiley, J. F., et al (1995) Regional, cellular, and subcellular variations in the distribution of D1 and D2 dopamine receptors in primate brain. Journal of Neuroscience, 15, 7821–7836.CrossRefGoogle Scholar
Bischoff, S., Heinrich, M., Sonntag, J. M., et al (1986) The D1 receptor antagonist SCH 23390 also interacts potently with brain serotonin (5-HT2) receptors. European Journal of Pharmacology, 129, 367–370.Google Scholar
Bond, R. A., Leff, P., Johnston, T. D., et al (1995) Physiological effects of inverse agonists in transgenic mice with overexpression of the β2-adrenoceptor. Nature, 374, 272–276.Google Scholar
Breier, A. (1995) Serotonin, schizophrenia and antipsychotic drug action. Schizophrenia Research, 14, 187–202.CrossRefGoogle ScholarPubMed
Brown, C. M., Kilpatrick, A. T., Martin, A., et al (1988) Cerebral ischaemia reduces the density of 5-HT2 binding sites in the frontal cortex of the gerbil. Neuropharmacology, 27, 831–836.CrossRefGoogle ScholarPubMed
Brunello, N., Masotto, C., Steardo, L., et al (1995) New insights into the biology of schizophrenia through the mechanism of action of clozapine. Neuropsychopharmacology, 13, 177–213.CrossRefGoogle ScholarPubMed
Buckland, P. R., O'Donovan, M. C. & McGuffin, P. (1992) Changes in dopamine D1, D2 and D3 receptor mRNA levels in rat brain following antipsychotic treatment. Psychopharmacology, 106, 479–483.Google Scholar
Buckland, P. R., O'Donovan, M. C. & McGuffin, P. (1993) Clozapine and sulpiride up-regulate dopamine D3 receptor mRNA levels. Neuropharmacology, 32, 901–907.Google Scholar
Buckland, P. R., D'Souza, U., Maher, N. A. & McGuffin, P. (1997) The effects of antipsychotic drugs on the mRNA levels of serotonin 5-HT2A and 5-HT2C receptors. Molecular Brain Research, 48, 45–52.CrossRefGoogle ScholarPubMed
Bunzel, R., Blümcke, I., Cichon, S., et al (1998) Polymorphic imprinting of the serotonin2A (5-HT2A) receptor gene in human adult brain. Molecular Brain Research, 59, 90–92.Google Scholar
Burnet, P. W. J., Eastwood, S. L. & Harrison, P. J. (1994) Detection and quantitation of 5-HT1A and 5-HT2A receptor mRNAs in human hippocampus using a reverse transcriptase-polymerase chain reaction (RT-PCR) technique and their correlation with binding site densities and age. Neuroscience Letters, 178, 85–89.Google Scholar
Burnet, P. W. J. & Harrison, P. J. (1995) Genetic variation of the 5-HT2A receptor and response to clozapine. Lancet, 346, 909.Google ScholarPubMed
Burnet, P. W. J., Eastwood, S. L., Lacey, K. & Harrison, P. J. (1995a) The distribution of 5-HT1A and 5-HT2A receptor mRNAs in human brain. Brain Research, 676, 157–168.Google Scholar
Burnet, P. W. J., Mead, A., Eastwood, S. L., et al (1995b) Repeated ECS differentially affects rat brain 5-HT1A and 5-HT2A receptor expression. Neuroreport, 6, 901–904.CrossRefGoogle ScholarPubMed
Burnet, P. W. J., Eastwood, S. L. & Harrison, P. J. (1996a) 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology, 15, 442–455.Google Scholar
Burnet, P. W. J., Chen, C. P. L.-H., McGowan, S., et al (1996b) The effects of clozapine and haloperidol on serotonin-1A, −2A and −2C receptor gene expression and serotonin metabolism in the rat forebrain. Neuroscience, 73, 531–540.Google Scholar
Chen, K., Yang, W., Grimsby, J., et al (1992) The human 5-HT2 receptor is encoded by a multiple intron-exon gene. Molecular Brain Research, 14, 20–26.CrossRefGoogle ScholarPubMed
Cheng, A. V. T., Ferrier, I. N., Morris, C. M., et al (1991) Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer's and Parkinson's diseases. Journal of the Neurological Sciences, 106, 50–55.CrossRefGoogle ScholarPubMed
Civelli, O., Bunzow, J. R. & Grandy, D. K. (1993) Molecular diversity of the dopamine receptors. Annual Review of Pharmacology and Toxicology, 33, 281–307.Google Scholar
Damask, S. P., Bovenkerk, K. A., de la Pena, G., et al (1996) Differential effects of clozapine and haloperidol on dopamine receptor mRNA expression in rat striatum and cortex. Molecular Brain Research, 41, 241–249.Google Scholar
Dean, B. & Hayes, W. L. (1996) Decreased frontal cortical serotonin2A receptors in schizophrenia. Schizophrenia Research, 21, 133–139.CrossRefGoogle ScholarPubMed
Dean, B. & Hayes, W. L., Opeskin, K., et al (1996) Serotonin2 receptors and the serotonin transporter in the schizophrenic brain. Behavioural Brain Research, 73, 169–175.Google Scholar
Dean, B., Pavey, G. & Opeskin, K. (1997) [3H]raclopride binding to brain tissue from subjects with schizophrenia: methodological aspects. Neuropharmacology, 36, 779–786.Google Scholar
Deutch, A. Y., Moghaddam, B., Innis, R. B., et al (1991) Mechanisms of action of atypical antipsychotic drugs. Implications for novel therapeutic strategies for schizophrenia. Schizophrenia Research, 4, 121–156.Google Scholar
Ding, D., Toth, M., Zhou, Y., et al (1993) Glial cell specific expression of the serotonin2 receptor gene: Selective reactivation of a repressed promoter. Molecular Brain Research, 20, 181–191.CrossRefGoogle Scholar
D'Souza, U., McGuffin, P. & Buckland, P. R. (1997) Antipsychotic regulation of dopamine D1, D2 and D3 receptor mRNA. Neuropharmacology, 36, 1689–1696.Google Scholar
Egan, C. T., Herrick-Davis, K. & Teitler, M. (1998) Creation of a constitutively activated state of the 5-hydroxytryptamine2A receptor by site-directed mutagenesis: inverse agonist activity of antipsychotic drugs. Journal of Pharmacology and Experimental Therapeutics, 286, 85–90.Google ScholarPubMed
Eisen, A. S. & Mullins, U. L. (1996) Regulation of central 5-HT2A receptors: a review of in vivo studies. Behavioural Brain Research, 73, 177–181.CrossRefGoogle Scholar
Engel, G., Muller-Schweinitzer, E. & Palacios, J. M. (1984) 2-[125lodo]LSD, a new ligand for the characterization and localization of 5-HT2 receptors. Naunyn-Schmiedebergs Archives of Pharmacology, 325, 328–336.CrossRefGoogle Scholar
Ferry, R. C., Unsworth, C. D., Artmyshyn, R. P., et al (1994) Regulation of mRNA encoding 5-HT2A receptors in P11 cells through a post-transcriptional mechanism requiring activation of protein kinase C. Journal of Biological Chemistry, 269, 31850–31857.CrossRefGoogle ScholarPubMed
Florijn, W. J., Tarazi, F. I. & Creese, I. (1997) Dopamine receptor subtypes: differential regulation after 8 months treatment with antipsychotic drugs. Journal of Pharmacology and Experimental Therapeutics, 280, 561–569.Google Scholar
Fox, C. A., Mansour, A. & Watson, S. J. Jr (1994) The effects of haloperidol on dopamine receptor gene expression. Experimental Neurology, 130, 288–303.Google Scholar
Garlow, S. J. & Ciaranello, R. D. (1995) Transcriptional control of the rat serotonin2 receptor gene. Molecular Brain Research, 31, 201–209.CrossRefGoogle ScholarPubMed
Grotewiel, M. S. & Sanders-Bush, E. (1994) Regulation of serotonin2A receptors in heterologous expression systems. Journal of Neurochemistry, 63, 1255–1260.Google Scholar
Gurevich, E. V. & Joyce, J. N. (1997) Alterations in the cortical serotonergic system in schizophrenia: a post mortem study. Biological Psychiatry, 42, 529–545.Google Scholar
Gurevich, E. V., Bordeion, Y., Shapiro, R. M., et al (1997) Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study. Archives of General Psychiatry, 54, 225–232.Google Scholar
Hall, H., Farde, L. & Sedvall, G. (1988) Human dopamine receptor subtypes – in vitro binding analysis using 3H-SCH 23390 and 3H-raclopride. Journal of Neural Transmission, 73, 7–21.CrossRefGoogle ScholarPubMed
Harrington, K. A., Augood, S. J., Faull, R. L. M., et al (1995) Dopamine D1 receptor, D2 receptor, proenkephalin A and substance P gene expression in the caudate nucleus of control and schizophrenic tissue: a quantitative cellular in situ hybridisation study. Molecular Brain Research, 33, 333–342.Google Scholar
Harrison, P. J. (1995) In vitro brain imaging: techniques for studying and localizing the pathogenesis of psychiatric diseases. In Neurobiology and Psychiatry, vol. 3 (ed. Kerwin, R.W.), pp. 157–174. Cambridge: Cambridge University Press.Google Scholar
Harrison, P. J. (1996) Advances in post mortem molecular neurochemistry and neuropathology: examples from schizophrenia research. British Medical Bulletin, 52, 527–538.Google Scholar
Harrison, P. J. (1999) Neuropathological effects of antipsychotics and other treatments. In The Neuropathology of Schizophrenia and its Interpretation (eds P. J. Harrison & G.W Roberts). Oxford: Oxford University Press (in press).Google Scholar
Harrison, P. J. & Geddes, J. R. (1996) Schizophrenia and the 5-HT2a receptor gene. Lancet, 347, 1274.Google Scholar
Harrison, P. J. & Burnet, P. W. J. (1997) The 5-HT2A (serotonin2A) receptor gene in the aetiology, pathophysiology and pharmacotherapy of schizophrenia. Journal of Psychopharmacology, 11, 21–23.Google Scholar
Helmeste, D. M., Tang, S. W., Bunney, W. E. Jr, et al (1996) Decrease in σ but no increase in striatal dopamine D4 sites in schizophrenic brains. European Journal of Pharmacology, 314, R3–R5.Google Scholar
Hidaka, K., Tada, S., Matsumoto, M., et al (1996) YM-50001: A novel, potent and selective dopamine D4 receptor antagonist. Neuroreport, 7, 2543–2546.Google Scholar
Hoyer, D. & Boddeke, H. W. G. M. (1993) Partial agonists, full agonists, antagonists: dilemmas of definition. Trends in Pharmacological Sciences, 14, 270–275.Google Scholar
Huang, N., Ase, A. R., Hebert, C., et al (1997) Effects of chronic neuroleptic treatments on dopamine D1 and D2 receptors: homogenate binding and autoradiographic studies. Neurochemistry International, 30, 277–290.Google Scholar
Huntley, G. W., Morrison, J. H., Prikholzhan, A., et al (1992) Localization of multiple dopamine receptor subtype mRNAs in human and monkey cortex and striatum. Molecular Brain Research, 15, 181–188.Google Scholar
Hurley, M. J., Stubbs, C. M., Jenner, P., et al (1996) Effect of chronic treatment with typical and atypical neuroleptics on the expression of dopamine D2 and D3 receptors in rat brain. Psychopharmacology, 128, 362–370.Google Scholar
Jakab, R. L. & Goldman-Rakic, P. S. (1998) 5-hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: Possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proceedings of the National Academy of Sciences of the United States of America, 95, 735–740.Google Scholar
Joyce, J. N., Shane, A., Lexow, N., et al (1993) Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology, 8, 215–336.Google Scholar
Julius, D., Huang, K. N., Livelli, T. J., et al (1990) The 5-HT2 receptor defines a family of structurally distinct but functionally conserved serotonin receptors. Proceedings of the National Academy of Sciences of the United States of America, 87, 928–932.Google Scholar
Kahn, R. S. & Davis, K. L. (1995) New developments in dopamine and schizophrenia. In Psychopharmacology: The Fourth Generation of Progress (eds Bloom, F. E. & Kupfer, D. J.), pp. 1193–1203. New York: Academic Press.Google Scholar
Kanes, S. J., Hitzemann, B. A. & Hitzemann, R. J. (1993) On the relationship between D2 receptor density and neuroleptic-induced catalepsy among eight inbred strains of mice. Journal of Pharmacology and Experimental Therapeutics, 267, 538–547.Google Scholar
Kao, H.-T., Adham, N., Olsen, M. A., et al (1992) Site directed mutagenesis of a single residue changes the binding properties of the serotonin 5-HT2 receptor from a human to a rat pharmacology. FEBS Letters, 307, 324–328.Google Scholar
Kapur, S. & Remington, G. (1996) Serotonindopamine interaction and its relevance to schizophrenia. American Journal of Psychiatry, 153, 466–476.Google Scholar
Kenakin, T., Morgan, P. & Lutz, M. (1995) On the importance of the “antagonist assumption” to how receptors express themselves. Biochemical Pharmacology, 50, 17–26.Google Scholar
Kerwin, R. W. & Collier, D. (1996) The dopamine D4 receptor in schizophrenia: an update. Psychological Medicine, 26, 221–227.Google Scholar
Kinon, B. J. & Lieberman, J. A. (1996) Mechanisms of action of atypical antipsychotic drugs: a critical analysis. Psychopharmacology, 124, 2–34.Google Scholar
Knable, M. B., Hyde, T. M., Herman, M. M., et al (1994) Quantitative autoradiography of dopamine-D1 receptors, D2 receptors, and dopamine uptake sites in postmortem striatal specimens from schizophrenic patients. Biological Psychiatry, 36, 827–835.CrossRefGoogle ScholarPubMed
Knable, M. B., Hyde, T. M., Murray, A. M., et al (1996) A postmortem study of frontal cortical dopamine D1 receptors in schizophrenics, psychiatric controls, and normal controls. Biological Psychiatry, 40, 1191–1199.Google Scholar
Kouzmenko, A. P., Hayes, W. L., Pereira, A., et al (1997) 5-HT2A receptor polymorphism and steady state receptor expression in schizophrenia. Lancet, 349, 1815.Google Scholar
Kramer, M. S., Last, B., Getson, A., et al (1997) The effects of a selective D4 dopamine receptor antagonist (L-745, 870) in acutely psychotic patients with schizophrenia. Archives of General Psychiatry, 54, 567–572.Google Scholar
Kuoppomaki, M., Palvimaki, E.-P., Hietala, J., et al (1995) Differential regulation of rat 5-HT2A and 5-HT2C receptors after chronic treatment with clozapine, chlorpromazine and three putative atypical antipsychotic drugs. Neuropsychopharmacology, 13, 139–150.Google Scholar
Lahti, R. A., Roberts, R. C. & Tamminga, C. A. (1995) D2-Family receptor distribution in human postmortem tissue: an autoradiographic study. Neuroreport, 6, 2505–2512.Google Scholar
Lahti, R. A., Roberts, R. C., Conley, R. R., et al (1996a) Dopamine D2, D3, D4 receptors in human postmortem brain sections: comparison between normals and schizophrenics (abstract). Schizophrenia Research, 18, 173.Google Scholar
Lahti, R. A., Primus, R. J., Gallagher, D. W., et al (1996b) Distribution of dopamine D4 receptor in human postmortem brain sections: autoradiographic studies with [3H]-NGD-94-l (Abstract). Schizophrenia Research, 18, 173.Google Scholar
Lamelle, M., Abi-Dargham, A. & Casanova, M. F. (1993) Selective abnormalities of prefrontal serotonergic receptors in schizophrenia. Archives of General Psychiatry, 50, 810–818.Google Scholar
Lee, T. & Tang, S. W. (1984) Loxapine and clozapine decrease serotonin (S2) but do not elevate dopamine (D2) receptor numbers in the rat brain. Psychiatry Research, 12, 277–285.Google Scholar
Lévesque, D., Martres, M.-P., Diaz, J., et al (1995) A paradoxical regulation of the dopamine D3 receptor expression suggests the involvement of an anterograde factor from dopamine neurons. Proceedings of the National Academy of Sciences of the United States of America, 92, 1719–1723.Google Scholar
Lewis, D. A. & Anderson, S. A. (1995) The functional architecture of the prefrontal cortex and schizophrenia. Psychological Medicine, 25, 887–894.Google Scholar
Leysen, J. E., Niemegeers, C. J. E., Tollenaere, J. P., et al (1978) Serotonergic component of neuroleptic receptors. Nature, 272, 168–171.Google Scholar
Leysen, J. E., Niemegeers, C. J. E., van Nueten, J. M., et al (1982) [3H]Ketanserin (R41468), a selective 3H-ligand for serotonin, receptor binding sites. Molecular Pharmacology, 21, 301–314.Google Scholar
Leysen, J. E., Janssen, P. M. F., Schotte, A., et al (1993) Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: Role of 5HT2 receptors. Psychopharmacology, 112 (suppl.), S40–S54.Google Scholar
Lidow, M. S. & Goldman-Rakic, P. S. (1994) A common action of clozapine, haloperidol, and remoxipride on D1 and D2-dopaminergic receptors in the primate cerebral cortex. Proceedings of the National Academy of Sciences of the United States of America, 91, 4353–4356.Google Scholar
Leysen, J. E., Birnbaum, S. G. & Goldman-Rakic, P. S. (1995) Clozapine, haloperidol and remoxipride differentially regulate 5HT2-serotonergic sites in the primate cerebral cortex (abstract). Schizophrenia Research, 15, 158.Google Scholar
Leysen, J. E., & Goldman-Rakic, P. S. (1997) Differential regulation of D2 and D4 receptor mRNAs in the primate cerebral cortex vs. neostriatum: effects of chronic treatment with typical and atypical antipsychotic drugs. Journal of Pharmacology and Experimental Therapeutics, 283, 939–946.Google Scholar
Leysen, J. E., Elsworth, J. D. & Goldman-Rakic, P. S. (1997) Down-regulation of the D1 and D5 dopamine receptors in the primate prefrontal cortex by chronic treatment with antipsychotic drugs. Journal of Pharmacology and Experimental Therapeutics, 281, 597–603.Google Scholar
Lin, M.-W., Curtis, D., Williams, N., et al (1995) Suggestive evidence for linkage of schizophrenia to markers on chromosome 13q14.1-q32. Psychiatric Genetics, 5, 117–126.Google Scholar
López-Gimenez, J. F., Vilaró, M. J., Palacios, J. M., et al (1998) [3H] MDL 100,907 labels 5-HT2A serotonin receptors selectively in primate brain. Neuropharmacology, 37, 1147–1158.Google Scholar
Lucaites, V. L., Nelson, D. L., Wainscott, D. B., et al (1996) Receptor subtype and density determine the coupling repertoire of the 5-HT2 receptor subfamily. Life Sciences, 59, 1081–1085.Google Scholar
Lundqvist, C., Halldin, C., Ginovart, N., et al (1996) [“C]MDL 100907, a radioligand for selective imaging of 5-HT2A receptors with positron emission tomography. Life Sciences, 58, PL187–PL192.Google Scholar
Mackay, A. V. P., Doble, A., Bird, E. D., et al (1978) 3H-spipendone binding in normal and schizophrenic postmortem human brain. Life Sciences, 23, 527–532.Google Scholar
Marcusson, J., Morgan, D. G., Winblad, B., et al (1984) Serotonin2-binding sites in human frontal cortex and hippocampus. Selective loss of S2A sites with age. Brain Research, 311, 51–56.Google Scholar
Marzella, P. L., Hill, C., Keks, N., et al (1997) The binding of both [3H]nemonapride and [3H]raclopride is increased in schizophrenia. Biological Psychiatry, 42, 648–654.Google Scholar
Matsubara, S. & Meltzer, H. Y. (1989) Effect of typical and atypical antipsychotic drugs on 5-HT2 receptor density in rat cerebral cortex. Life Sciences, 45, 1397–1406.Google Scholar
Matsumoto, M., Hidaka, K., Tada, S., et al (1996) Low levels of mRNA for dopamine D4 receptor in human cerebral cortex and striatum. Journal of Neurochemistry, 66, 915–919.Google Scholar
Meador-Woodruff, J. H., Grandy, D. K., Van Tol, H. H. M., et al (1994a) Dopamine receptor gene expression in the human medial temporal lobe. Neuropsychopharmacology, 10, 239–248.Google Scholar
Meador-Woodruff, J. H., Damask, S. P. & Watson, S. J. Jr (1994b) Differential expression of autoreceptors in the ascending dopamine systems of the human brain. Proceedings of the National Academy of Sciences of the United States of America, 91, 8297–8301.Google Scholar
Meador-Woodruff, J. H., Haroutunian, V., Powchik, P., et al (1997) Dopamine receptor transcript expression in striatum and prefrontal and occipital cortex. Focal abnormalities in orbitofrontal cortex in schizophrenia. Archives of General Psychiatry, 54, 1089–1095.Google Scholar
Meltzer, H. Y. (1992) The importance of serotonin-dopamine interactions in the action of clozapine. British Journal of Psychiatry, 160 (suppl. 17), 46–53.Google Scholar
Mengod, G., Vilaro, M. T., Raurich, A., et al (1996) 5-HTreceptors in mammalian brain: receptor autoradiography and in situ hybridization studies of new ligands and newly identified receptors. Histochemical Journal, 28, 747–758.Google Scholar
Mikuni, M. & Meltzer, H. Y. (1984) Reduction of serotonin2 receptors in rat cerebral cortex after subchronic administration of imipramine, chlorpromazine, and the combination thereof. Life Sciences, 34, 87–92.Google Scholar
Mita, Y., Hanada, S., Nishino, M., et al (1986) Decreased serotonin S2 and increased dopamine D2 receptors in chronic schizophrenics. Biological Psychiatry, 21, 1407–1414.Google Scholar
Mrzljak, L., Bergson, C., Pappy, M., et al (1996) Localization of dopamine D4 receptors in GABAergic neurons of the primate brain. Nature, 381, 245–248.Google Scholar
Mulcrone, J. & Kerwin, R. W. (1996) No difference in the expression of the D4 gene in postmortem frontal cortex from controls and schizophrenics. Neuroscience Letters, 219, 163–166.Google Scholar
Murray, A. M., Ryoo, H. L., Gurevich, E., et al (1994) Localization of dopamine D3 receptors to mesolimbic and D2 receptors to mesostriatal regions of human forebrain. Proceedings of the National Academy of Sciences of the United States of America, 91, 11271–11275.Google Scholar
Murray, A. M., Hyde, T. M., Knable, M. B., et al (1995) Distribution of putative D4 dopamine receptors in postmortem striatum from patients with schizophrenia. Journal of Neuroscience, 15, 2186–2191.Google Scholar
Newman-Tancredi, A., Conte, C., Chaput, C., et al (1997) Agonist and inverse agonist efficacy at human recombinant serotonin 5-HT1A receptors as a function of receptor: G protein stoichiometry. Neuropharmacology, 36, 451–459.CrossRefGoogle ScholarPubMed
O'Dell, S. J., La Hoste, G. J., Widmark, C. B., et al (1990) Chronic treatment with clozapine or haloperidol differentially regulates dopamine and serotonin receptors in rat brain. Synapse, 6, 146–153.Google Scholar
Okubo, Y., Suhara, T., Suzuki, K., et al (1997) Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature, 385, 634–636.Google Scholar
Owen, F., Cross, A. J., Crow, T. J., et al (1981) Neurotransmitter receptors in brain in schizophrenia. Acta Psychiatrica Scandinavica, (suppl. 291), 20–26.CrossRefGoogle Scholar
Peroutka, S. J. (1994) Molecular biology of serotonin (5-HT) receptors. Synapse, 18, 241–260.Google Scholar
Reynolds, G. P. (1996a) The importance of dopamine D4 receptors in the action and development of antipsychotic agents. Drugs, 51, 7–11.Google Scholar
Reynolds, G. P. (1996b) Dopamine D4 receptor in schizophrenia? Journal of Neurochemistry, 66, 881–882.Google Scholar
Reynolds, G. P., Garrett, N. J., Rupniak, N., et al (1983a) Chronic clozapine treatment of rats down-regulates cortical 5-HT2 receptors. European Journal of Pharmacology, 89, 325–328.Google Scholar
Reynolds, G. P., Rossor, M. N. & Iversen, L. L. (1983b) Preliminary studies of human cortical 5-HT2 receptors and their involvement in schizophrenia and neuroleptic drug action. Journal of Neural Transmission, (suppl. 18), 273–277.Google Scholar
Reynolds, G. P., Arnold, L., Rossor, M. N., et al (1984) Reduced binding of [3H]ketanserin to cortical 5-HT2 receptors in senile dementia of the Alzheimer type. Neuroscience Letters, 44, 47–51.Google Scholar
Reynolds, G. P. & Mason, S. L. (1994) Are striatal dopamine D4 receptors increased in schizophrenia? Journal of Neurochemistry, 63, 1576–1577.Google Scholar
Reynolds, G. P. & Mason, S. L. (1995) Absence of detectable striatal dopamine D4 receptors in drug-treated schizophrenia. European Journal of Pharmacology, 281, R5–R6.Google Scholar
Rinaldi-Carmona, M., Bouaboula, M., Congy, C., et al (1993) Up-regulation of 5-HT2 receptors in the rat brain by repeated administration of SR 46349B, a selective 5-HT_2 receptor antagonist. European Journal of Pharmacology (Molecular Pharmacology), 246, 73–80.Google Scholar
Ritter, L. M. & Meador-Woodruff, J. H. (1997) Antipsychotic regulation of hippocampal dopamine receptor messenger RNA expression. Biological Psychiatry, 42, 155–164.Google Scholar
Roberts, D. A., Balderson, D., Pickering-Brown, S. M., et al (1996) The relative abundance of dopamine D4 receptor mRNA in post mortem brains of schizophrenics. Schizophrenia Research, 20, 171–174.Google Scholar
Rosier, A., Dupont, P., Peuskens, J., et al (1996) Visualisation of loss of 5-HT2A receptors with age in healthy volunteers using [18F]altanserin and positron emission tomographic imaging. Psychiatry Research Neuroimaging, 68, 11–22.Google Scholar
Roth, B. L., Hamblin, M. & Ciaranello, R. D. (1990) Regulation of 5-HT2 and 5-HT1C serotonin receptor levels. Methodology and mechanisms. Neuropsychopharmacology, 3, 427–433.Google Scholar
Roth, B. L. & Meltzer, H. Y. (1995) The role of serotonin in schizophrenia. In Psychopharmacology: The Fourth Generation of Progress (eds Bloom, F. E. & Kupfer, D. J.), pp. 1215–1227. New York: Raven Press.Google Scholar
Saltzman, A. G., Morse, B., Whitman, M. M., et al (1991) Cloning of the human serotonin 5-HT2 and 5-HT1C receptor subtypes. Biochemical and Biophysical Research Communications, 181, 1469–1478.Google Scholar
Sanders-Bush, E. (1990) Adaptive regulation of central serotonin receptors linked to phosphoinositide hydrolysis. Neuropsychopharmacology, 3, 411–416.Google Scholar
Saucier, C. & Albert, P. R. (1997) Identification of an endogenous 5-hydroxytryptamine2A receptor in NIH-3T3 cells: Agonist-induced down-regulation involves decreases in receptor RNA and number. Journal of Neurochemistry, 68, 1998–2001.Google Scholar
Schmauss, C. (1996) Enhanced cleavage of an atypical intron of dopamine D3-receptor pre mRNA in chronic schizophrenia. Journal of Neuroscience, 16, 7902–7909.Google Scholar
Schmauss, C., Haroutunian, V., Davis, K. L., et al (1993) Selective loss of dopamine D3-type receptor mRNA expression in parietal and motor cortices of patients with chronic schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 90, 8942–8946.Google Scholar
Schmidt, C. J., Sorensen, S. M., Kehne, J. H., et al (1995) The role of 5-HT2A receptors in antipsychotic activity. Life Sciences, 56, 2209–2222.Google Scholar
Schoots, O., Seeman, P., Guan, H.-C., et al (1995) Long-term haloperidol elevated dopamine D4 receptors by 2-fold in rats. European Journal of Pharmacology (Molecular Pharmacology), 289, 67–72.Google Scholar
Sedvall, G. & Farde, L. (1995) Chemical brain anatomy in schizophrenia. Lancet, 346, 743–749.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 Sciences of the United States of America, 86, 10156–10160.Google Scholar
Seeman, P., Niznik, H. B. (1990) Dopamine receptors and transporters in Parkinson's disease and schizophrenia. FASEB Journal, 4, 2737–2744.Google Scholar
Seeman, P., Guan, H.-G. & Van Tol, H. H. M. (1993) Dopamine D4 receptors elevated in schizophrenia. Nature, 365, 441–445.CrossRefGoogle ScholarPubMed
Seeman, P., Guan, H.-G. & Van Tol, H. H. M. (1995) Schizophrenia: elevation of dopamine D4-like sites, using [3H]nemonapride and [125l]epidepride. European Journal of Pharmacology, 286, R3–R5.Google Scholar
Seeman, P. & Van Tol, H. H. M. (1995) Dopamine D4-like receptor elevation in schizophrenia: Cloned D2 and D4 receptors cannot be discriminated by raclopride competition against [3H]nemonapride. Journal of Neurochemistry, 64, 1413–1415.Google Scholar
Seeman, P., Corbett, R. & Van Tol, H. H. M. (1997a) Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors. Neuropsychopharmacology 16, 93–110.Google Scholar
Seeman, P., Guan, H.-G., Nobrega, J., et al (1997b) Dopamine D2-like sites in schizophrenia, but not in Alzheimer's, Huntington's, or control brains, for [3H]benzquinoline. Synapse, 25, 137–146.Google Scholar
Sokoloff, P., Martres, M.-P., Giros, B., et al (1990) The third dopamine receptor (D3) as a novel target for antipsychotics. Biochemical Pharmacology, 43, 659–666.CrossRefGoogle Scholar
Spurlock, G., Heils, A., Holmans, P., et al (1998) A family based association study of TI02C polymorphism in 5-HT2A and schizophrenia plus identification of a new polymorphism in the promoter. Molecular Psychiatry, 3, 42–49.Google Scholar
Stam, N. J., Van Huizen, F., Van Alebeek, C., et al (1992) Genomic organisation, coding sequence and functional expression of human 5-HT2 and 5-HT1A receptor genes. European Journal of Pharmacology (Molecular Pharmacology), 227, 153–162.Google Scholar
Stefanis, N. C., Bresnick, J. N., Kerwin, R. W., et al (1998) Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain. Molecular Brain Research, 53, 112–119.Google Scholar
Sumiyoshi, T., Stockmeier, C. A., Overholser, J. C., et al (1995) Dopamine D4 receptors and effects of guanine nucleotides on [3H]raclopride binding in postmortem caudate nucleus of subjects with schizophrenia or major depression. Brain Research, 681, 109–116.Google Scholar
Sumiyoshi, T., Ichikawa, J. & Meltzer, H. Y. (1997) The effect of streptozotocin-induced diabetes on dopamine2, serotonin1A and serotonin2A receptors in the rat brain. Neuropsychopharmacology 16, 211–216.Google Scholar
Tarazi, F. I., Florijn, W. J. & Creese, I. (1997) Differential regulation of dopamine receptors after chronic typical and atypical antipsychotic drug treatment. Neuroscience, 78, 985–996.Google Scholar
Todd, K. G., McManus, D. J. & Baker, G. B. (1995) Chronic administration of the antidepressants phenelzine, desipramine, clomipramine, or maprotiline decreased binding to 5-hydroxytryptamine2A receptors without affecting benzodiazepine binding sites in rat brain. Cellular and Molecular Neurobiology, 15, 361–370.Google Scholar
Toth, M. & Shenk, T. (1994) Antagonist-mediated down-regulation of 5-hydroxytryptamine type 2 receptor gene expression: Modulation of transcription. Molecular Pharmacology, 45, 1095–1100.Google Scholar
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
Van Tol, H. H. M., Wu, C. M., Guan, H.-C., et al (1992) Multiple dopamine D4 receptor variants in the human population. Nature, 358, 149–152.Google Scholar
Wang, W., Hahn, K.-H., Bishop, J. F., et al (1996) Up-regulation of D3 dopamine receptor mRNA by neuroleptics. Synapse, 23, 232–235.Google Scholar
Weinberger, D. R. & Lipska, B. K. (1995) Cortical maldevelopment, antipsychotic drugs, and schizophrenia: a search for common ground. Schizophrenia Research, 16, 87–110.Google Scholar
Whitaker, P. M., Crow, T. J. & Ferrier, I. N. (1981) Tritated LSD binding in frontal cortex in schizophrenia. Archives of General Psychiatry, 38, 278–280.Google Scholar
Williams, J., Spurlock, G., McGuffin, P., et al (1996) Association between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene. Lancet, 347, 1294–1296.Google Scholar
Williams, J., McGuffin, P., Nothen, M., et al (1997) Meta analysis of association between the 5-HT2a receptor T102C polymorphism and schizophrenia. Lancet, 349, 1221.Google Scholar
Wilmot, C. A. & Szczepanik, A. M. (1989) Effects of acute and chronic treatments with clozapine and haloperidol on serotonin (5-HT2) and dopamine (D2) receptors in the rat brain. Brain Research, 487, 288–298.Google Scholar
Zakzanis, K. K. & Hansen, K. T. (1998) Dopamine D2 densities and the schizophrenic brain. Schizophrenia Research, 32, 201–206.Google Scholar
Zhou, Q.-S., Chen, K. & Shih, J. C. (1995) Characterization of the human 5-HT2A receptor gene promoter. Journal of Neuroscience, 15, 4885–4895.Google Scholar
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