All Roads to Schizophrenia Lead to Dopamine Supersensitivity and Elevated Dopamine D2High Receptors

CNS Neuroscience and Therapeutics

Volumn 17, Issue 2, 2011, Pages 118-132

  Seeman, Philip ^a  

^a UNIVERSITY OF TORONTO   (Canada)

Author keywords

Antipsychotics; D2High receptors; Dopamine D2 receptor; Dopamine supersensitivity; Psychosis; Schizophrenia

Indexed keywords

4 AMINOBUTYRIC ACID; ACETYLCHOLINE; AMOXAPINE; AMPHETAMINE; ARIPIPRAZOLE; BIFEPRUNOX; BIOLOGICAL MARKER; CHLORPROMAZINE; CLOZAPINE; COCAINE; CORTICOSTERONE; DOPAMINE; DOPAMINE 2 RECEPTOR; DOPAMINE 3 RECEPTOR; DOPAMINE 4 RECEPTOR; FLUPHENAZINE; GLUTAMIC ACID; MELPERONE; METHYLPHENIDATE; N METHYL DEXTRO ASPARTIC ACID; NEUROLEPTIC AGENT; NORADRENALIN; PERPHENAZINE; PHENCYCLIDINE; PSYCHOSTIMULANT AGENT; QUETIAPINE; REMOXIPRIDE; STEROID; THIORIDAZINE; ZIPRASIDONE;

ANOXIA; BIRTH INJURY; BRAIN DAMAGE; CESAREAN SECTION; DENSITY; DOPAMINE RELEASE; DRUG SENSITIZATION; GENE DELETION; GENETIC RISK; HUMAN; HYPOTHESIS; IN VIVO STUDY; NONHUMAN; PARKINSONISM; PSYCHOSIS; RELAPSE; REVIEW; SCHIZOPHRENIA; SOCIAL ISOLATION; SUPERSENSITIVITY; TARDIVE DYSKINESIA;

ANIMALS; ANTIPSYCHOTIC AGENTS; BRAIN; DISEASE MODELS, ANIMAL; DOPAMINE; GENE EXPRESSION REGULATION; HUMANS; RECEPTORS, DOPAMINE D2; SCHIZOPHRENIA;

EID: 79952642829     PISSN: 17555930     EISSN: 17555949     Source Type: Journal    
DOI: 10.1111/j.1755-5949.2010.00162.x     Document Type: Review

References (105)

1. Lieberman JA, Kane JM, Alvir J. Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology (Berl) 1987;91:415-433.
2. Curran C, Byrappa N, McBride A. Stimulant psychosis: Systematic review. Brit J Psychiat 2004;185:196-204.
3. Laruelle M. Imaging synaptic neurotransmission with in vivo binding competition techniques: A critical review. J Cereb Blood Flow Metab 2000;20:423-451.
4. Zemlan FP, Hirschowitz J, Garver DL. Relation of clinical symptoms to apomorphine-stimulated growth hormone release in mood-incongruent psychotic patients. Arch Gen Psychiat 1986;43:1162-1167.
5. Seeman P, Nam D, Ulpian C, Liu IS, Tallerico T. New dopamine receptor, D2Longer, with unique TG splice site, in human brain. Brain Res Mol Brain Res 2000;76:132-141.
6. Seeman P. Targeting the dopamine D2 receptor in schizophrenia. Expert Opin Ther Targets 2006;10:515-531.
7. High receptors. Synapse 2007;61:1013-1018.
8. Van Rossum JM. Different types of sympathomimetic alpha-receptors. J Pharm Pharmacol 1965;17:202-216.
9. Van Rossum JM. The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. Arch Int Pharmacodyn Ther 1966;160:492-494.
10. Van Rossum JM. The significance of dopamine-receptor blockade for the action of neuroleptic drugs. In: Brill H, Cole JO, Deniker P, Hippius H, Bradley PB, editors. Neuro-Psycho-Pharmacology, Proceedings of the Fifth International Congress of the Collegium Internationale Neuro-Psycho-pharmacologicum Amsterdam Excerpta Medica Foundation, 1967;321-329.
11. Van Rossum JM, Hurkmans JAThM. Mechanism of action of psychomotor stimulant drugs. Significance of dopamine in locomotor stimulant action. Int J Neuropharmacol 1964;3:227-239.
12. Seeman P, Wong M, Lee T. Dopamine receptor-block and nigral fiber-impulse blockade by major tranquilizers. Fed Proc 1974;33:246 Abstr 243.
13. Seeman P, Chau-Wong M, Tedesco J, Wong K. Brain receptors for antipsychotic drugs and dopamine: Direct binding assays. Proc Natl Acad Sci USA 1975;72:4376-4380.
14. Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 1976;261:717-719.
15. 3H]haloperidol. Psychopharmacol Commun 1975;1:663-673.
16. 3H]dopamine binding associated with dopamine receptors in calf brain membranes. Mol Pharmacol 1976;12:800-812.
17. 2 dopamine receptor cDNA. Nature 1988;336:783-787.
18. Spano PF, Govoni S, Trabucchi M. Studies on the pharmacological properties of dopamine receptors in various areas of the central nervous system. Adv Biochem Psychopharmacol 1978;19:155-165.
19. Kebabian JW, Calne DB. Multiple receptors for dopamine. Nature 1979;277:93-96.
20. Seeman P. Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1987;1:133-152.
21. Seeman P. Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2, clozapine occupies D4. Neuropsychopharmacology 1992;7:261-284.
22. Seeman P. Atypical antipsychotics: Mechanism of action. Can J Psychiatry 2002;47:27-38.
23. Seeman P. Dopamine and schizophrenia. Scholarpedia 2007;2:3634. Available from: [Accessed 12 April 2010.
24. 11C]-(+)-PHNO. Arch Gen Psychiatry 2009;66:606-615.
25. Lecrubier Y. A partial D3 receptor agonist in schizophrenia. Neuropsychopharmacology 2003;13:S167-S168.
26. Seeman P. Antipsychotic drugs, dopamine receptors, and schizophrenia. Clin Neurosci Res 2001;1:53-60.
27. 4 receptor with high affinity for the antipsychotic clozapine. Nature 1991;350:610-614.
28. Seeman P, Corbett R, Van Tol HH. Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors. Neuropsychopharmacology 1997;16:93-110.
29. 3H-spiperone depend on tissue concentration: Analysis and examples. J Neurochem 1984;43:221-235.
30. Seeman P, Van Tol HHM. Deriving the therapeutic concentrations for clozapine and haloperidol: The apparent dissociation constant of a neuroleptic at the dopamine D2 or D4 receptor varies with the affinity of the competing radioligand. Eur J Pharmacol-Mol Pharmacol Section 1995;291:59-66.
31. Seeman P. Dopamine D2 receptors as treatment targets in schizophrenia. Clin Schizophrenia & Related Psychoses 2010;4:56-73.
32. Seeman P. Glutamate and dopamine components in schizophrenia. J Psychiatry Neurosci 2009;34:143-149.
33. Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: A randomized Phase 2 clinical trial. Nat Med 2007;13:1102-1107.
34. High receptor. Synapse 2009;63:935-939.
35. Seeman P, Ulpian C, Bergeron C, et al. Bimodal distribution of dopamine receptor densities in brains of schizophrenics. Science 1984;225:728-731.
36. high dopamine receptors. Synapse 2006;60:319-346.
37. George SR, Watanabe M, Di Paolo T, Falardeau P, Labrie F, Seeman P. The functional state of the dopamine receptor in the anterior pituitary is in the high-affinity form. Endocrinology 1985;117:690-697.
38. High states, implying many paths to psychosis. Proc Natl Acad Sci USA 2005;102:3513-3518.
39. High receptors and marked supersensitivity to the dopamine agonist (+)PHNO. Synapse 2009;63:247-251.
40. High receptors in rats reared in social isolation. Synapse 2009;63:476-483.
41. Giannini AJ, Nageotte C, Loiselle RH, Malone DA, Price WA. Comparison of chlorpromazine, haloperidol and pimozide in the treatment of phencyclidine psychosis: DA-2 receptor specificity. J Toxicol Clin Toxicol 1984;22:573-579.
42. 11C]-(+)-PHNO. Biol Psychiat 2006;59:389-394.
43. Sibley DR, Mahan LC, Creese I. Dopamine receptor binding on intact cells. Absence of a high-affinity agonist-receptor binding state. Mol Pharmacol 1983;23:295-302.
44. Skinbjerg M, Namkung Y, Halldin C, Innis RB, Sibley DR. Pharmacological characterization of 2-methoxy-N-propylnorapomorphine's interactions with D2 and D3 dopamine receptors. Synapse 2009;63:462-475.
45. High receptors on intact cells. Synapse 2008;62:314-318.
46. Bhardwaj SK, Beaudry G, Quirion R, Levesque D, Srivastava LK. Neonatal ventral hippocampus lesion leads to reductions in nerve growth factor inducible-B mRNA in the prefrontal cortex and increased amphetamine response in the nucleus accumbens and dorsal striatum. Neuroscience 2003;122:669-676.
47. high receptors, reversed by general anesthesia: Relation to relapse? Synapse 2004;52:77-83.
48. Wolinsky TD, Swanson CJ, Smith KE, et al. The Trace Amine 1 receptor knockout mouse: An animal model with relevance to schizophrenia. Genes Brain Behav 2007;6:628-639.
49. High receptors in methamphetamine-sensitized rats. Eur J Neurosci 2008;27:2551-2557.
50. High receptors. Eur Neuropsychopharmacol 2008;18:551-556.
51. High receptors in the striatum of rats sensitized to caffeine motor effects. Synapse 2008;62:394-397.
52. High receptors in alpha-1b-adrenoceptor knockout supersensitive mice. Synapse 2007;61:569-572.
53. Sumiyoshi T, Seeman P, Uehara T, Itoh H, Tsunoda M, Kurachi M. Increased proportion of high-affinity dopamine D2 receptors in rats with excitotoxic damage of the entorhinal cortex, an animal model of schizophrenia. Brain Res Mol Brain Res 2005;140:116-119.
54. Lipska BK, Lerman DN, Khaing ZZ, Weinberger DR. The neonatal ventral hippocampal lesion model of schizophrenia: Effects on dopamine and GABA mRNA markers in the rat midbrain. Eur J Neurosci 2003;18:3097-3104.
55. High receptors in the striatum. Synapse 2009;63:443-446.
56. High receptors in knockouts of the dopamine transporter and the vesicular monoamine transporter may contribute to spontaneous hyperactivity and dopamine supersensitivity. Synapse 2007;61:573-576.
57. 11C]-(+)-PHNO, a new agonist radiotracer for imaging the high-affinity state of D2 receptors in vivo using positron emission tomography. J Neurochem 2006;97:1089-1103.
58. 11C]raclopride. Synapse 2006;59:260-269.
59. 11C]MNPA. Synapse 2009;63:378-389.
60. 3H]raclopride are indistinguishably inhibited by D2 agonists and antagonists ex vivo. Nucl Med Biol 2008;35:11-17.
61. McCormick PN, Kapur S, Reckless G, Wilson AA. Ex vivo[11C]-(+)-PHNO binding is unchanged in animal models displaying increased high-affinity states of the D2 receptor in vitro. Synapse 2009;63:998-1009.
62. 3H-(-)-N-n-propylnorapomorphine in mouse brain. Naunyn Schmiedebergs Arch Pharmacol 1989;340:13-20.
63. High receptors measured ex vivo are elevated in amphetamine-sensitized animals. Synapse 2009;63:186-192.
64. von Zastrow M, Kobilka BK. Ligand-regulated internalization and recycling of human beta 2-adrenergic receptors between the plasma membrane and endosomes containing transferrin receptors. J Biol Chem 1992;267:3530-3538.
65. Insel PA, Mahan LC, Motulsky HJ, Stoolman LM, Koachman AM. Time-dependent decreases in binding affinity of agonists for beta-adrenergic receptors of intact S49 lymphoma cells. A mechanism of desensitization. J Biol Chem 1983;258:13597-13605.
66. Fujita N, Nakahiro M, Fukuchi I, Saito K, Yoshida H. Effects of pertussis toxin on D2-dopamine receptor in rat striatum: Evidence for coupling of Ni regulatory protein with D2-receptor. Brain Res 1985;333:231-236.
67. Hirvonen J, van Erp TG, Huttunen J, et al. Increased caudate dopamine D2 receptor availability as a genetic marker for schizophrenia. Arch Gen Psychiatry 2005;62:371-378.
68. Corripio I, Perez V, Catafau AM, Mena E, Carrio I, Alvarez E. Striatal D2 receptor binding as a marker of prognosis and outcome in untreated first-episode psychosis. Neuroimage 2006;29:662-666.
69. Kellendonk C, Simpson EH, Polan HJ, et al. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron 2006;49:603-615.
70. High. Schizophrenia Res 2009;91:191-192.
71. Baumeister AA, Francis JL. Historical development of the dopamine hypothesis of schizophrenia. J Hist Neurosci 2002;11:265-277.
72. Delay J, Deniker P, Harl J-M. Traitement des états d'excitation et d'agitation par une méthode médicamenteuse dérivée de l'hibernithérapie. [Therapeutic method derived from hiberno-therapy in excitation and agitation states]. Ann Méd-Psychol (Paris) 1952;110:267-273.
73. Agid O, Kapur S, Arenovich T, Zipursky RB. Delayed-onset hypothesis of antipsychotic action: A hypothesis tested and rejected. Arch Gen Psychiatry 2003;60:1228-1235.
74. Agid O, Seeman P, Kapur S. The 'delayed onset' of antipsychotic action - an idea whose time has come and gone. J Psychiatry Neurosci 2006;31:93-100.
75. Kapur S, Arenovich T, Agid O, Zipursky R, Lindborg S, Jones B. Evidence for onset of antipsychotic effects within the first 24 hours of treatment. Am J Psychiatry 2005;162:939-946.
76. Leucht S, Busch R, Hamann J, Kissling W, Kane JM. Early-onset hypothesis of antipsychotic drug action: A hypothesis tested, confirmed and extended. Biol Psychiatry 2005;57:1543-1549.
77. Anderson WH, Kuehnle JC, Catanzano DM. Rapid treatment of acute psychosis. Am J Psychiatry 1976;133:1076-1078.
78. Carter RG. Psychotolysis with haloperidol. Rapid control of the acutely disturbed psychotic patient. Dis Nerv Syst. 1977;38:237-239.
79. Glovinsky D, Kirch DG, Wyatt RJ. Early antipsychotic response to resumption of neuroleptics in drug-free chronic schizophrenic patients. Biol Psychiatry 1992;31:968-970.
80. Keck PE Jr., Cohen BM, Baldessarini RJ, McElroy SL. Time course of antipsychotic effects of neuroleptic drugs. Am J Psychiatry 1989;146:1289-1292.
81. Emsley R, Rabinowitz J, Medori R. Time course for antipsychotic treatment response in first-episode schizophrenia. Am J Psychiatry 2006;163:743-745.
82. Lieberman J, Jody D, Geisler S, et al. Time course and biologic correlates of treatment response in first-episode schizophrenia. Arch Gen Psychiatry 1993;50:369-376.
83. 2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 1992;49:538-544.
84. 2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 1999;156:286-293.
85. Meltzer HY, Huang M. In vivo actions of atypical antipsychotic drug on serotonergic and dopaminergic systems. Prog Brain Res 2008;172:177-197.
86. Seeman P, Tallerico T. Rapid release of antipsychotic drugs from dopamine D2 receptors: An explanation for low receptor occupancy and early clinical relapse upon drug withdrawal of clozapine or quetiapine. Am J Psychiat 1999;156:876-884.
87. 2 receptor explain the action of atypical antipsychotics?- A new hypothesis. Am J Psychiatry 2001;158:360-369.
88. Lee T, Seeman P. Elevation of brain neuroleptic/dopamine receptors in schizophrenia. Am J Psychiatry 1980;137:191-197.
89. 11C]raclopride. Arch Gen Psychiatry 1990;47:213-219.
90. 11C]N-methylspiperone. Psychiatry Res 1995;61:67-83.
91. Glatt SJ, Faraone SV, Tsuang MT. Meta-analysis identifies an association between the dopamine D2 receptor gene and schizophrenia. Mol Psychiat 2003;8:911-915.
92. Glatt SJ, Jönsson EG. The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: Evidence from fixed- and random-effects meta-analyses. Am J Med Genet B Neuropsychiatr Genet 2006;141:149-154.
93. Allen NC, Bagade S, McQueen MB, et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: The SzGene database. Nat Genet 2008;40:827-834.
94. Chouinard G, Jones BD, Annable L. Neuroleptic-induced supersensitivity psychosis. Am J Psychiatry 1978;135:1409-1410.
95. Chouinard G. Severe cases of neuroleptic-induced supersensitivity psychosis. Diagnostic criteria for the disorder and its treatment. Schizophr Res 1991;5:21-33.
96. Chouinard G, Jones BD. Schizophrenia as dopamine-deficiency disease. Lancet 1978; II :99-100.
97. Chouinard G, Jones BD. Evidence of brain dopamine deficiency in schizophrenia. Can J Psychiatr 1979;24:661-667.
98. Miller R, Chouinard G. Loss of striatal cholinergic neurons as a basis of tardive and L-dopa-induced dyskinesias, and neuroleptic-induced supersensitivity psychosis. Biol Psychiatry 1993;34:713-738.
99. Chouinard G, Miller R. A new Rating Scale for Psychotic Symptoms (RSPS). Part I. Theoretical Principles and Subscale 1: Perception Symptoms (Hallucinations and Illusions). Schizophrenia Res 1999;38:101-122.
100. Chouinard G, Chouinard VA. Atypical antipsychotics: CATIE study, drug-induced movement disorder and resulting iatrogenic psychiatric-like symptoms, supersensitivity rebound psychosis and withdrawal discontinuation syndromes. Psychother Psychosom 2008;77:69-77.
101. Mizrahi R, Rusjan P, Agid O, Graff A, Mamo DC, Zipursky RB, Kapur S. Adverse subjective experience with antipsychotics and its relationship to striatal and extrastriatal D2 receptors: A PET study in schizophrenia. Am J Psychiatry 2007;164:630-637.
102. 11C]-(+)-PHNO PET study. Neuropsychopharmacology 2009;34:1078-1086.
103. Fell MJ, Perry KW, Falcone JF, et al. In vitro and in vivo evidence for a lack of interaction with dopamine D2 receptors by the metabotropic glutamate 2/3 receptor agonists 1S, 2S, 5R, 6S-2-aminobicyclo[3.1.0]hexane-2, 6-bicaroxylate monohydrate (LY354740) and (-)-2-oxa-4-aminobicyclo[3.1.0] Hexane-4, 6-dicarboxylic acid (LY379268). J Pharmacol Exp Ther 2009;331:1126-1136.
104. Seeman N, Seeman P. Psychosis: Discovery of the antipsychotic receptor. Toronto SZ Publications, 2009;148.
105. Seeman P. Tardive dyskinesia, dopamine receptors, and neuroleptic damage to cell membranes. J Clin Psychopharmacol 1988;8(4 Suppl):3S-9S.