P Seeman

Summary

Affiliation: University of Toronto
Country: Canada

Publications

  1. ncbi Dopamine D(2) receptor blockade by haloperidol. (3)H-raclopride reveals much higher occupancy than EEDQ
    S Kapur
    Schizophrenia Program, CAMH, Ontario, Toronto, Canada
    Neuropsychopharmacology 23:595-8. 2000
  2. ncbi An update of fast-off dopamine D2 atypical antipsychotics
    Philip Seeman
    Am J Psychiatry 162:1984-5. 2005
  3. ncbi Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert
    G Novak
    Department of Pharmacology, Medical Sciences Building, University of Toronto, Room 4344, Medical Science Building, 8 Taddle Creek Road, Ontario, M5S 1A8, Toronto, Canada
    Brain Res Mol Brain Res 107:183-9. 2002
  4. ncbi Brain region binding of the D2/3 agonist [11C]-(+)-PHNO and the D2/3 antagonist [11C]raclopride in healthy humans
    Ariel Graff-Guerrero
    PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
    Hum Brain Mapp 29:400-10. 2008
  5. ncbi Increased dopamine D2High receptors in knockouts of the dopamine transporter and the vesicular monoamine transporter may contribute to spontaneous hyperactivity and dopamine supersensitivity
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
    Synapse 61:573-6. 2007
  6. doi Are dopamine D2 receptors out of control in psychosis?
    Philip Seeman
    Department of Pharmacology, University of Toronto, 260 Heath Street, West, Unit 605, Toronto, Ontario M5P 3L6, Canada Department of Psychiatry, University of Toronto, 260 Heath Street, West, Unit 605, Toronto, Ontario, M5P 3L6, Canada Electronic address
    Prog Neuropsychopharmacol Biol Psychiatry 46:146-52. 2013
  7. doi Loss of dopamine neuron terminals in antipsychotic-treated schizophrenia; relation to tardive dyskinesia
    Philip Seeman
    Department of Pharmacology, University of Toronto, 260 Heath Street West, Unit 605, Toronto M5P 3L6, Ontario, Canada
    Prog Neuropsychopharmacol Biol Psychiatry 44:178-83. 2013
  8. pmc Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: increased dopamine D2 receptor dimerization
    Min Wang
    Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON, Canada
    Mol Brain 3:25. 2010
  9. ncbi Dopamine D2 and D3 receptors in human putamen, caudate nucleus, and globus pallidus
    Philip Seeman
    Department of Pharmacology, University of Toronto, King s College Circle, Medical Sciences Building, Toronto, Ontario, Canada M5S 1A8
    Synapse 60:205-11. 2006
  10. ncbi Consistent with dopamine supersensitivity, RGS9 expression is diminished in the amphetamine-treated animal model of schizophrenia and in postmortem schizophrenia brain
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
    Synapse 61:303-9. 2007

Research Grants

  1. RECEPTORS MEDIATING DRUG DEPENDENCE
    Philip Seeman; Fiscal Year: 1999
  2. RECEPTORS FOR COCAINE AND DOPAMINE
    Philip Seeman; Fiscal Year: 1993

Collaborators

Detail Information

Publications100

  1. ncbi Dopamine D(2) receptor blockade by haloperidol. (3)H-raclopride reveals much higher occupancy than EEDQ
    S Kapur
    Schizophrenia Program, CAMH, Ontario, Toronto, Canada
    Neuropsychopharmacology 23:595-8. 2000
    ....
  2. ncbi An update of fast-off dopamine D2 atypical antipsychotics
    Philip Seeman
    Am J Psychiatry 162:1984-5. 2005
  3. ncbi Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert
    G Novak
    Department of Pharmacology, Medical Sciences Building, University of Toronto, Room 4344, Medical Science Building, 8 Taddle Creek Road, Ontario, M5S 1A8, Toronto, Canada
    Brain Res Mol Brain Res 107:183-9. 2002
    ....
  4. ncbi Brain region binding of the D2/3 agonist [11C]-(+)-PHNO and the D2/3 antagonist [11C]raclopride in healthy humans
    Ariel Graff-Guerrero
    PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
    Hum Brain Mapp 29:400-10. 2008
    ..This differential binding of agonist vs. antagonist radioligand, especially in the critically important region of the limbic striatum/pallidum, offers new avenues to investigate the role of the dopamine system in health and disease...
  5. ncbi Increased dopamine D2High receptors in knockouts of the dopamine transporter and the vesicular monoamine transporter may contribute to spontaneous hyperactivity and dopamine supersensitivity
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
    Synapse 61:573-6. 2007
  6. doi Are dopamine D2 receptors out of control in psychosis?
    Philip Seeman
    Department of Pharmacology, University of Toronto, 260 Heath Street, West, Unit 605, Toronto, Ontario M5P 3L6, Canada Department of Psychiatry, University of Toronto, 260 Heath Street, West, Unit 605, Toronto, Ontario, M5P 3L6, Canada Electronic address
    Prog Neuropsychopharmacol Biol Psychiatry 46:146-52. 2013
    ..Finally, haloperidol reduces the number of D2High receptors that are elevated by amphetamine, indicating that this therapeutic effect may occur clinically. ..
  7. doi Loss of dopamine neuron terminals in antipsychotic-treated schizophrenia; relation to tardive dyskinesia
    Philip Seeman
    Department of Pharmacology, University of Toronto, 260 Heath Street West, Unit 605, Toronto M5P 3L6, Ontario, Canada
    Prog Neuropsychopharmacol Biol Psychiatry 44:178-83. 2013
    ....
  8. pmc Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: increased dopamine D2 receptor dimerization
    Min Wang
    Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON, Canada
    Mol Brain 3:25. 2010
    ....
  9. ncbi Dopamine D2 and D3 receptors in human putamen, caudate nucleus, and globus pallidus
    Philip Seeman
    Department of Pharmacology, University of Toronto, King s College Circle, Medical Sciences Building, Toronto, Ontario, Canada M5S 1A8
    Synapse 60:205-11. 2006
    ..The present findings are in good agreement with the known gene expression data for D2 and D3 receptors in these human brain regions...
  10. ncbi Consistent with dopamine supersensitivity, RGS9 expression is diminished in the amphetamine-treated animal model of schizophrenia and in postmortem schizophrenia brain
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
    Synapse 61:303-9. 2007
    ..The reduced levels of RGS9-2 expression in both an animal model of schizophrenia and a postmortem schizophrenia brain provide further evidence implicating RGS9-2 as a candidate gene in schizophrenia...
  11. ncbi Anesthetics inhibit high-affinity states of dopamine D2 and other G-linked receptors
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario M5S JA8, Canada
    Synapse 50:35-40. 2003
    ....
  12. doi Dopamine D2(High) receptors moderately elevated by sertindole
    Philip Seeman
    Department of Pharmacology, Medical Science Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8
    Synapse 62:389-93. 2008
    ..Although the findings suggest that rats or patients treated with sertindole might exhibit behavioral dopamine supersensitivity, the drug-induced increase in D2(High) receptors was less than that previously found with haloperidol...
  13. ncbi Dopamine displaces [3H]domperidone from high-affinity sites of the dopamine D2 receptor, but not [3H]raclopride or [3H]spiperone in isotonic medium: Implications for human positron emission tomography
    Philip Seeman
    Department of Pharmacology, University of Toronto, 1 King s College Circle, Medical Sciences Building Room 4344, Toronto, Ontario, Canada M5S JA8
    Synapse 49:209-15. 2003
    ....
  14. ncbi Link between dopamine D1 and D2 receptors in rat and human striatal tissues
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8
    Synapse 47:250-4. 2003
    ....
  15. doi Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High receptors: D2 basis for schizophrenia
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
    Synapse 62:819-28. 2008
    ....
  16. ncbi Amphetamine-sensitized animals show a marked increase in dopamine D2 high receptors occupied by endogenous dopamine, even in the absence of acute challenges
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8
    Synapse 46:235-9. 2002
    ....
  17. doi Dopamine D2(High) receptors moderately elevated by bifeprunox and aripiprazole
    Philip Seeman
    Department of Pharmacology, Medical Science Building, University of Toronto, Toronto, Ontario, Canada
    Synapse 62:902-8. 2008
    ..Future research needs to test directly whether long-term treatment with dopamine partial agonists leads to any behavioral dopamine supersensitivity...
  18. doi Glutamate receptor mGlu2 and mGlu3 knockout striata are dopamine supersensitive, with elevated D2(High) receptors and marked supersensitivity to the dopamine agonist (+)PHNO
    Philip Seeman
    Department of Pharmacology, Medical Science Building, University of Toronto, 1 King s College Circle, Toronto, Ontario, Canada
    Synapse 63:247-51. 2009
    ..Such regulation may contribute to the antipsychotic action of mGlu2/3 receptor agonists...
  19. doi Dopamine D2(High) receptors on intact cells
    Philip Seeman
    Department of Pharmacology, Medical Science Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8
    Synapse 62:314-8. 2008
    ....
  20. ncbi Alcohol-withdrawn animals have a prolonged increase in dopamine D2high receptors, reversed by general anesthesia: relation to relapse?
    Philip Seeman
    Department of Pharmacology, University of Toronto, Medical Science Building, Toronto, Ontario M5S 1A8, Canada
    Synapse 52:77-83. 2004
    ..General anesthesia may alleviate aspects of alcohol or amphetamine abuse or psychosis associated with elevated D2High...
  21. ncbi Psychosis pathways converge via D2high dopamine receptors
    Philip Seeman
    Department of Pharmacology, University of Toronto, and Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5S 1A8
    Synapse 60:319-46. 2006
    ..Dopamine supersensitivity, in turn, correlates with D2High states. The finding that all antipsychotics, traditional and recent ones, act on D2High dopamine receptors further supports the proposition...
  22. ncbi Targeting the dopamine D2 receptor in schizophrenia
    Philip Seeman
    University of Toronto, Pharmacology Department, Faculty of Medicine, Medical Science Building, Room 4344, 1 King s College Circle, Toronto, M5S 1A8, Canada
    Expert Opin Ther Targets 10:515-31. 2006
    ....
  23. ncbi Dopamine partial agonist action of (-)OSU6162 is consistent with dopamine hyperactivity in psychosis
    Philip Seeman
    Department of Pharmacology, Medical Science Building 4344, University of Toronto, 1 King s College Circle, Toronto, Ontario, Canada M5S 1A8
    Eur J Pharmacol 557:151-3. 2007
    ..While not excluding the possibility that dopamine underactivity may exist in the mesocortical system in psychosis, the antipsychotic action of (-)-OSU6162 is consistent with dopamine overactivity in psychosis...
  24. ncbi Increased dopamine D2(High) receptors in amphetamine-sensitized rats, measured by the agonist [(3)H](+)PHNO
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
    Synapse 61:263-7. 2007
    ..2-3.5-fold increase of DA D2(High) receptors may explain why amphetamine-sensitized animals are much more sensitive to DA agonists, even though the total density of D2 receptors may apparently be unchanged or even decreased...
  25. ncbi Dopamine agonist action of phencyclidine
    Philip Seeman
    Departments of Pharmacology and Psychiatry, University of Toronto, Medical Science Building, Ontario, Canada
    Synapse 58:275-7. 2005
    ..This strong dopamine-like agonist action at the functional high-affinity state of the dopamine D2 receptor by the phencyclidine psychotomimetic is consistent with the dopamine hypothesis of psychosis...
  26. ncbi Memantine agonist action at dopamine D2High receptors
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8
    Synapse 62:149-53. 2008
    ..Because the memantine potencies at NMDA receptors and dopamine D2(High) receptors are of a similar order of magnitude, it is likely that the clinical features of memantine can be attributed to its action at both types of receptors...
  27. ncbi Dopamine partial agonist actions of the glutamate receptor agonists LY 354,740 and LY 379,268
    Philip Seeman
    Department of Pharmacology, Medical Science Building 4344, University of Toronto, Toronto, Ontario, Canada M5S 1A8
    Synapse 62:154-8. 2008
    ..The dopamine agonist and antagonist actions of these compounds indicate that these drugs have properties of a dopamine partial agonist, and may, therefore, have antipsychotic action...
  28. ncbi Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics
    P Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
    Mol Psychiatry 10:877-83. 2005
    ..Because these drugs have a combined action on both dopamine receptors and NMDA receptors, these drugs, when given in vivo, test a combined hyperdopamine and hypoglutamate theory of psychosis...
  29. pmc Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis
    Philip Seeman
    Pharmacology Department, Medical Science Building, Room 4344, University of Toronto, 1 King s College Circle, Toronto, ON, Canada M5S 1A8
    Proc Natl Acad Sci U S A 102:3513-8. 2005
    ..If many types of brain impairment cause dopamine behavioral supersensitivity and a common increase in D2High states, it suggests that there are many pathways to psychosis, any one of which can be disrupted...
  30. ncbi Comment on "Diverse psychotomimetics act through a common signaling pathway"
    Philip Seeman
    Departments of Pharmacology, and Psychiatry, 1 King s College Circle, University of Toronto, Toronto, Ontario, Canada M5S 1A8
    Science 305:180; author reply 180. 2004
  31. pdf Atypical antipsychotics: mechanism of action
    Philip Seeman
    Departments of Pharmacology and Psychiatry, University of Toronto, Toronto, Ontario
    Can J Psychiatry 47:27-38. 2002
    ..To understand how these drugs work, it is important to examine the atypical antipsychotics' mechanism of action and how it differs from that of the more typical drugs...
  32. ncbi Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of dopamine: a hypothesis
    Philip Seeman
    Department of Pharmacology, University of Toronto, Medical Science Building, Room 4344, 8 Taddle Creek Road, Ont, Canada M5S 1A8
    Behav Brain Res 130:79-83. 2002
    ..These high levels of resting and pulsatile dopamine cause widespread stimulation of post-synaptic dopamine receptors, overcoming any concomitant presynaptic inhibition of dopamine release...
  33. doi Glutamate agonists for treating schizophrenia have affinity for dopamine D2High and D3 receptors
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
    Synapse 63:705-9. 2009
    ..The findings indicate that this type of glutamate agonist, LY 379,268, has a significant affinity for D2(High) and D3 receptors...
  34. doi Dopamine D2 receptors as treatment targets in schizophrenia
    Philip Seeman
    Pharmacology Department, Faculty of Medicine, University of Toronto, Canada
    Clin Schizophr Relat Psychoses 4:56-73. 2010
    ..Future goals include imaging D2High receptors and desensitizing them in early-stage psychosis...
  35. doi All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2(high) receptors
    Philip Seeman
    Departments of Pharmacology and Psychiatry, University of Toronto, 260 Heath Street West, Suite 605, Toronto, Ontario, Canada M5P 3L6
    CNS Neurosci Ther 17:118-32. 2011
    ..The D2 receptor can exist in a state of high-affinity (D2(High) ) or in a state of low-affinity for dopamine (D2Low)...
  36. ncbi Antiparkinson therapeutic potencies correlate with their affinities at dopamine D2(High) receptors
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
    Synapse 61:1013-8. 2007
    ..Bromocriptine, cabergoline, lergotrile, pergolide, and pramipexole had no affinity for D1(High), consistent with the clinical observations that the D2-selective bromocriptine and pramipexole elicit low levels of dyskinesia...
  37. doi Alzheimer's disease: β-amyloid plaque formation in human brain
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
    Synapse 65:1289-97. 2011
    ..Several immune approaches and a cholesterol-lowering strategy are also being tested to remove the β-amyloids...
  38. doi Glutamate agonist LY404,039 for treating schizophrenia has affinity for the dopamine D2(High) receptor
    Philip Seeman
    Department of Pharmacology, Medical Science Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8
    Synapse 63:935-9. 2009
    ..A possible clinical antipsychotic action of LY404,039 may depend on the combined stimulation of glutamate receptors and a partial dopamine agonist action that would interfere with neurotransmission at D2(High) receptors...
  39. doi Dopamine agonist radioligand binds to both D2High and D2Low receptors, explaining why alterations in D2High are not detected in human brain scans
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Canada M5P 3L6
    Synapse 66:88-93. 2012
    ..Thus, the radio-agonist label for (+)PHNO is not selective for dopamine D2High receptors, but also binds to the D2Low state of the dopamine receptor...
  40. doi Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil
    Philip Seeman
    Department of Pharmacology, Medical Science Building, University of Toronto, Toronto, Ontario, Canada
    Synapse 63:698-704. 2009
    ..It is concluded that phencyclidine and other psychostimulants and hallucinogens can stimulate dopamine D2 receptors at concentrations related to their behavioral actions...
  41. pmc Glutamate and dopamine components in schizophrenia
    Philip Seeman
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
    J Psychiatry Neurosci 34:143-9. 2009
    ..Hence, the clinical antipsychotic action of a glutamate agonist may depend on its ability to interfere with DA neurotransmission by its DA partial agonism...
  42. ncbi Rapid release of antipsychotic drugs from dopamine D2 receptors: an explanation for low receptor occupancy and early clinical relapse upon withdrawal of clozapine or quetiapine
    P Seeman
    Department of Psychiatry, University of Toronto, Ont, Canada
    Am J Psychiatry 156:876-84. 1999
    ....
  43. ncbi Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine
    H H Van Tol
    Department of Pharmacology, University of Toronto, Ontario, Canada
    Nature 350:610-4. 1991
    ..Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs...
  44. ncbi A human serotonin-7 receptor pseudogene
    I H Qian
    Department of Pharmacology, Faculty of Medicine, University of Toronto, Medical Science Building, 8 Taddle Creek Road, Toronto, Ontario, Canada
    Brain Res Mol Brain Res 53:339-43. 1998
    ..It was concluded that this sequence represented a pseudogene related to the serotonin-7 receptor gene...
  45. ncbi Cloning and expression of a human somatostatin-14-selective receptor variant (somatostatin receptor 4) located on chromosome 20
    L L Demchyshyn
    Department of Psychiatry, University of Toronto, Canada
    Mol Pharmacol 43:894-901. 1993
    ..Natl. Acad. Sci. USA 89:11151-11155 (1992)], the two gene products possess distinctive pharmacological profiles and affinities for the SST agonists SMS 201-995 and MK-678...
  46. ncbi Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1
    R K Sunahara
    Department of Pharmacology, University of Toronto, Ontario, Canada
    Nature 350:614-9. 1991
    ..The existence of a dopamine D1-like receptor with these characteristics had not been predicted and may represent an alternative pathway for dopamine-mediated events and regulation of D2 receptor activity...
  47. ncbi Dopamine D2 receptors internalize in their low-affinity state
    F Ko
    Department of Pharmacology, Medical Science Building, Room 4344, University of Toronto, Toronto, Ont M5S 1A8
    Neuroreport 13:1017-20. 2002
    ....
  48. ncbi Dopamine D4 receptors elevated in schizophrenia
    P Seeman
    Pharmacology Department, University of Toronto, Ontario, Canada
    Nature 365:441-5. 1993
    ....
  49. ncbi Schizophrenia: normal sequence in the dopamine D2 receptor region that couples to G-proteins. DNA polymorphisms in D2
    P Seeman
    Department of Pharmacology, Clarke Institute of Psychiatry, University of Toronto, Ontario, Canada
    Neuropsychopharmacology 8:137-42. 1993
    ..However, exon 6 contained three DNA polymorphic base changes, and introns 4 and 5 revealed three missing bases and two polymorphic base changes, none of which would be expected to alter the D2 receptor protein in schizophrenia...
  50. ncbi Human dopamine D5 receptor pseudogenes
    T Nguyen
    Department of Pharmacology, University of Toronto, Ontario, Canada
    Gene 109:211-8. 1991
    ..Thus, the human genome contains at least two DRD5 pseudogenes, consistent with in situ human chromosomal hybridization analysis which reveals the presence of two pseudogenes...
  51. ncbi Schizophrenia: dopamine D1 receptor sequence is normal, but has DNA polymorphisms
    K Ohara
    Department of Pharmacology, Clarke Institute of Psychiatry, University of Toronto, Ontario, Canada
    Neuropsychopharmacology 8:131-5. 1993
    ..The D1 receptor genes were amplified by the polymerase chain reaction, subcloned, and sequenced. Although three DNA polymorphisms were found, the deduced amino acid sequence of the DA D1 receptor was normal in these tissues...
  52. ncbi A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy
    S Kapur
    Department of Psychiatry, University of Toronto, Ontario
    Arch Gen Psychiatry 57:553-9. 2000
    ..The following study was undertaken to explore these effects across the clinical dose range and relate this information to its clinical profile...
  53. ncbi A serotonin-4 receptor-like pseudogene in humans
    I S Liu
    Department of Pharmacology, Faculty of Medicine, University of Toronto, Medical Science Building, 8 Taddle Creek Road, Toronto, Ontario M5S 1A8, Canada
    Brain Res Mol Brain Res 53:98-103. 1998
    ..The predicted amino acid sequence of the human pseudogene is about 35% identical with that of the rat serotonin-4 receptor...
  54. ncbi A human somatostatin receptor (SSTR3), located on chromosome 22, displays preferential affinity for somatostatin-14 like peptides
    J D Corness
    Department of Psychiatry, University of Toronto, Ont, Canada
    FEBS Lett 321:279-84. 1993
    ....
  55. ncbi In vivo evidence for dopamine-mediated internalization of D2-receptors after amphetamine: differential findings with [3H]raclopride versus [3H]spiperone
    W Sun
    PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
    Mol Pharmacol 63:456-62. 2003
    ....
  56. ncbi Schizophrenia: elevated mRNA for dopamine D2(Longer) receptors in frontal cortex
    T Tallerico
    Department of Psychiatry, Faculty of Medicine, Medical Science Building, University of Toronto, Toronto, Canada M5S 1A8
    Brain Res Mol Brain Res 87:160-5. 2001
    ..It is possible, therefore, that the elevation of the mRNAs for D2(Longer), D2(Long) and D2(Short) in the frontal cortex may be related to the disease of schizophrenia itself...
  57. ncbi Antiparkinson concentrations of pramipexole and PHNO occupy dopamine D2(high) and D3(high) receptors
    Philip Seeman
    Department of Pharmacology, Medical Sciences Building, Toronto, Ontario, Canada
    Synapse 58:122-8. 2005
    ..The D3(High) receptors are less selectively occupied by +PHNO, bromocriptine, apomorphine, and -NPA...
  58. ncbi New dopamine receptor, D2(Longer), with unique TG splice site, in human brain
    P Seeman
    Department of Pharmacology, Medical Science Building, 8 Taddle Creek Road, University of Toronto, Toronto, Ontario, Canada
    Brain Res Mol Brain Res 76:132-41. 2000
    ..A new splice variant of the D2 receptor, D2(Longer), with a unique TG splice site, was found in one control brain and in two psychotic brains...
  59. doi The dopaminergic stabilizer ASP2314/ACR16 selectively interacts with D2(High) receptors
    Philip Seeman
    Clera Inc, 260 Heath Street West, Toronto, Ontario, Canada M5P 3L6
    Synapse 63:930-4. 2009
    ....
  60. ncbi Binding characteristics and sensitivity to endogenous dopamine of [11C]-(+)-PHNO, a new agonist radiotracer for imaging the high-affinity state of D2 receptors in vivo using positron emission tomography
    Nathalie Ginovart
    The Vivian Rakoff Positron Emission Tomography Unit, Center for Addiction and Mental Health, Toronto, Canada
    J Neurochem 97:1089-103. 2006
    ....
  61. pdf Dopamine D2High receptors measured ex vivo are elevated in amphetamine-sensitized animals
    Philip Seeman
    Clera Inc, 260 Heath Street West, Toronto, Ontario, Canada
    Synapse 63:186-92. 2009
    ..Therefore, it is recommended that this method of co-injecting the D2 radioligand and the dopamine agonist displacer be used in human positron tomography to detect D2(High) receptors in health and disease...
  62. ncbi NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia
    S Kapur
    Center for Addiction and Mental Health, Clarke Site, Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, Canada M5R 1T8
    Mol Psychiatry 7:837-44. 2002
    ..These findings confound the inferences one can draw from the ketamine/PCP models of schizophrenia...
  63. ncbi Dopamine D4 receptor variant, D4GLYCINE194, in Africans, but not in Caucasians: no association with schizophrenia
    P Seeman
    Department of Pharmacology, Clarke Institute of Psychiatry, Toronto, Canada
    Am J Med Genet 54:384-90. 1994
    ..The amino acid replacement occurs one amino acid away from a serine amino acid which is critical for the attachment of dopamine. None of the 147 Caucasians (113 controls; 34 schizophrenics) revealed this variant, termed D4GLYCINE194...
  64. ncbi Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: A new hypothesis
    S Kapur
    Schizophrenia Program and the PET Centre of the Centre for Addiction and Mental Health, University of Toronto, Canada
    Am J Psychiatry 158:360-9. 2001
    ..This article provides a new hypothesis about the mechanism of action of atypical antipsychotics...
  65. ncbi The human dopamine D5 receptor gene: cloning and characterization of the 5'-flanking and promoter region
    T V Beischlag
    Department of Pharmacology and Psychiatry, University of Toronto, Ontario, Canada
    Biochemistry 34:5960-70. 1995
    ....
  66. pmc A human serotonin 1D receptor variant (5HT1D beta) encoded by an intronless gene on chromosome 6
    L Demchyshyn
    Department of Psychiatry, University of Toronto, ON, Canada
    Proc Natl Acad Sci U S A 89:5522-6. 1992
    ..The 5HT1D beta gene maps to human chromosome 6. The existence of multiple neuronal 5HT1D-like receptors may help account for some of the complexities associated with [3H]serotonin binding patterns in native membranes...
  67. ncbi Dopamine D4 receptor variant in Africans, D4valine194glycine, is insensitive to dopamine and clozapine: report of a homozygous individual
    I S Liu
    Department of Pharmacology, Medical Sciences Building, Canada
    Am J Med Genet 61:277-82. 1996
    ..The one 15-year-old individual found homozygous for this variant also had sickle cell disease. The patient revealed an overall pattern of low weight and no axillary or pubic hair...
  68. ncbi Increasing D2 affinity results in the loss of clozapine's atypical antipsychotic action
    Shitij Kapur
    Department of Psychiatry, University of Toronto, Toronto M5S 3H6, Canada
    Neuroreport 13:831-5. 2002
    ..The implications for the design of future antipsychotics is discussed...
  69. doi Enhanced dopamine function in DISC1-L100P mutant mice: implications for schizophrenia
    T V Lipina
    Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Ontario, Canada
    Genes Brain Behav 9:777-89. 2010
    ..Taken together, our findings show the role of DISC1 in D(2) -related pathophysiological mechanism of schizophrenia, linking DISC1 with well-established DA hypothesis of schizophrenia...
  70. ncbi Kappa-opioid receptor stimulation quickens pathogenesis of compulsive checking in the quinpirole sensitization model of obsessive-compulsive disorder (OCD)
    Melissa L Perreault
    Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
    Behav Neurosci 121:976-91. 2007
    ..The animal model findings point to a potential role of kappa opioid systems in hastening the pathogenesis of OCD and to the possibility that distinct brain regions may mediate the development and the expression of compulsive checking...
  71. ncbi A transmembrane domain-derived peptide inhibits D1 dopamine receptor function without affecting receptor oligomerization
    S R George
    Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
    J Biol Chem 273:30244-8. 1998
    ..These findings represent the first demonstration that a peptide based on the transmembrane 6 of the D1DR may represent a novel category of noncompetitive D1DR antagonists...
  72. ncbi Increased expression of calcium/calmodulin-dependent protein kinase IIbeta in frontal cortex in schizophrenia and depression
    G Novak
    Department of Pharmacology, Medical Sciences Building Room 4344, University of Toronto, Ontario, Canada
    Synapse 59:61-8. 2006
    ..Because CaMKIIbeta influences the expression of many neuroreceptors and influences neural outgrowth and pruning, its altered expression in the cerebral cortex in schizophrenia or depression may contribute to these diseases...
  73. ncbi Antipsychotic pathway genes with expression altered in opposite direction by antipsychotics and amphetamine
    Françoise Ko
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8
    Synapse 60:141-51. 2006
    ..Of the 21 genes, 15 are not presently identified, and only 3 genes (cathepsin K, GRK6, and a gene with accession number AI177589) are located in chromosome regions known to be associated with schizophrenia...
  74. ncbi Idiopathic environmental intolerance: increased prevalence of panic disorder-associated cholecystokinin B receptor allele 7
    K Binkley
    Gage Occupational and Environmental Health Unit, University of Toronto, Toronto, Ontario, Canada
    J Allergy Clin Immunol 107:887-90. 2001
    ....
  75. pmc Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action
    S Kapur
    Department of Psychiatry, University of Toronto, Ont
    J Psychiatry Neurosci 25:161-6. 2000
    ..The objective of this study was to determine the relationship between kon, koff and the affinity (Ki) of antipsychotic agents for the D2 receptors, with particular reference to typical and atypical antipsychotic agents...
  76. ncbi Multiple dopamine D4 receptor variants in the human population
    H H Van Tol
    Laboratory for Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto, Ontario, Canada
    Nature 358:149-52. 1992
    ..Such variation among humans may underlie individual differences in susceptibility to neuropsychiatric disease and in responsiveness to antipsychotic medication...
  77. doi Less is more: antipsychotic drug effects are greater with transient rather than continuous delivery
    Anne Noël Samaha
    Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
    Biol Psychiatry 64:145-52. 2008
    ..Based on prior data, we predicted that variations in the within-day kinetics of antipsychotic drug delivery would produce different outcomes, even if we held achieved dose, route, and total duration of treatment constant...
  78. ncbi Dopamine D2 receptor radiotracers [(11)C](+)-PHNO and [(3)H]raclopride are indistinguishably inhibited by D2 agonists and antagonists ex vivo
    Patrick N McCormick
    Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8
    Nucl Med Biol 35:11-7. 2008
    ....
  79. ncbi First human evidence of d-amphetamine induced displacement of a D2/3 agonist radioligand: A [11C]-(+)-PHNO positron emission tomography study
    Matthaus Willeit
    Positron Emission Tomography Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
    Neuropsychopharmacology 33:279-89. 2008
    ..11)C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D(2/3) antagonist radioligands...
  80. ncbi Blockade of G protein-coupled receptors and the dopamine transporter by a transmembrane domain peptide: novel strategy for functional inhibition of membrane proteins in vivo
    Susan R George
    Department of Pharmacology, University of Toronto, Medical Sciences Building Room 4358, 1 King s College Circle, Toronto, Ontario M5S 1A8, Canada
    J Pharmacol Exp Ther 307:481-9. 2003
    ..The disruption of the hydrophobic core architecture of membrane proteins represents a novel mechanism of achieving functional inhibition that may be possible to exploit in developing novel therapeutics...
  81. ncbi "Breakthrough" dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time
    Anne Noël Samaha
    Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada M5T 1R8
    J Neurosci 27:2979-86. 2007
    ..These findings provide a model and a mechanism for antipsychotic treatment failure and suggest new directions for the development of more effective antipsychotics...
  82. doi Hyperactive mice show elevated D2(High) receptors, a model for schizophrenia: Calcium/calmodulin-dependent kinase II alpha knockouts
    Gabriela Novak
    Department of Pharmacology, Medical Science Building, Room 4345, University of Toronto, Toronto, Ontario, Canada M5S 1A8
    Synapse 64:794-800. 2010
    ..The elevated levels of CaMKIIbeta mRNA in the striatum suggest that this enzyme may increase D2(High) in animals and possibly in schizophrenia itself...
  83. ncbi Radiosynthesis, ex vivo and in vivo evaluation of [11C]preclamol as a partial dopamine D2 agonist radioligand for positron emission tomography
    Neil Vasdev
    PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada, M5T 1R8
    Synapse 60:314-8. 2006
    ..6). The binding potential value was only 0.34 over a 1 hour time course, suggesting that [11C]preclamol is not suitable for cerebral PET studies...
  84. ncbi Amphetamine sensitization elevates CaMKIIbeta mRNA
    Rachel Greenstein
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8
    Synapse 61:827-34. 2007
    ....
  85. ncbi High-affinity states of human brain dopamine D2/3 receptors imaged by the agonist [11C]-(+)-PHNO
    Matthaus Willeit
    Positron Emission Tomography Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada
    Biol Psychiatry 59:389-94. 2006
    ....
  86. ncbi Radiosynthesis and evaluation of [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron emission tomography
    Alan A Wilson
    PET Centre, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Ontario, Canada
    J Med Chem 48:4153-60. 2005
    ....
  87. ncbi Syntheses and in vitro evaluation of fluorinated naphthoxazines as dopamine D2/D3 receptor agonists: radiosynthesis, ex vivo biodistribution and autoradiography of [(18)F]F-PHNO
    Neil Vasdev
    PET Centre for Addiction and Mental Health, Toronto, Ontario, Canada, M5T 1R8
    Nucl Med Biol 34:195-203. 2007
    ..The present study reports the preparation and evaluation of fluorinated (+)-PHNO derivatives...
  88. ncbi Getting to the source of schizophrenia
    Philip Seeman
    Department of Pharmacology, University of Toronto
    Healthc Q 8:20. 2005
  89. ncbi Schizophrenia: elevated mRNA for calcium-calmodulin-dependent protein kinase IIbeta in frontal cortex
    G Novak
    Department of Pharmacology, Faculty of Medicine, Medical Science Building, University of Toronto, M5S 1A8, Toronto, Canada
    Brain Res Mol Brain Res 82:95-100. 2000
    ..The results indicate that the mRNA of this kinase is elevated in the schizophrenia frontal cortex...
  90. ncbi Cloning and characterization of additional members of the G protein-coupled receptor family
    D K Lee
    Department of Pharmacology, University of Toronto, Medical Sciences Building, Toronto, Ont, Canada
    Biochim Biophys Acta 1490:311-23. 2000
    ..PNR and GPR58 were expressed in COS cells, however no specific binding was observed for various serotonin receptor-specific ligands...
  91. ncbi Schizophrenia hippocampus has elevated expression of chondrex glycoprotein gene
    Carmen Chung
    Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
    Synapse 50:29-34. 2003
    ..The change in expression of the histamine-releasing factor gene suggests that this gene may be associated with the negative symptoms of impaired learning and memory in schizophrenia...
  92. ncbi Does nicotine affect D2 receptor upregulation? A case-control study
    S Silvestri
    Centre for Addictions and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
    Acta Psychiatr Scand 109:313-7; discussion 317-8. 2004
    ..The aim of this human positron emission tomography (PET) study was to compare upregulation in a smoker and a non-smoker, both of whom had received haloperidol for the same duration of time...
  93. ncbi "Extended" antipsychotic dosing: rationale and pilot data
    Gary Remington
    J Clin Psychopharmacol 25:611-3. 2005
  94. ncbi Elevated dopamine D2High receptors in alpha-1b-adrenoceptor knockout supersensitive mice
    Jean Pol Tassin
    Institut National de la Santé et de la Recherche Médicale Unité 114 et Centre National de la Recherche Scientifique UMR7148, College de France, 11 place Marcelin Berthelot, 75231 Paris Cedex 05, France
    Synapse 61:569-72. 2007
    ..9%, an increase of 2.3-fold. This elevation agrees with other types of DA-supersensitive animal striata and could assist in eliciting a supersensitive response in these alpha1b-adrenoceptor knockout mice...
  95. ncbi Glutamate agonists for schizophrenia stimulate dopamine D2High receptors
    Philip Seeman
    Schizophr Res 99:373-4. 2008
  96. ncbi Increased proportion of high-affinity dopamine D2 receptors in rats with excitotoxic damage of the entorhinal cortex, an animal model of schizophrenia
    Tomiki Sumiyoshi
    Department of Neuropsychiatry, Toyama Medical and Pharmaceutical University School of Medicine, 2630 Sugitani, Toyama 930 0194, Japan
    Brain Res Mol Brain Res 140:116-9. 2005
    ..These results provide a biochemical basis for behavioral supersensitivity in rats with EC lesions...
  97. pmc Cocaine self-administration produces a persistent increase in dopamine D2 High receptors
    Lisa A Briand
    Neuroscience Program, The University of Michigan, United States
    Eur Neuropsychopharmacol 18:551-6. 2008
    ..This may also help explain why stimuli that increase dopamine neurotransmission, including drugs themselves, are so effective in producing relapse in individuals with a history of exposure to cocaine...
  98. doi Increase of dopamine D2(High) receptors in the striatum of rats sensitized to caffeine motor effects
    Nicola Simola
    Department of Toxicology and Centre of Excellence for Neurobiology of Dependence, University of Cagliari, 09124 Cagliari, Italy
    Synapse 62:394-7. 2008
    ..This marked elevation in D2(High) receptors may account for the caffeine-induced behavioral dopamine supersensitivity and may help elucidate the interactions between caffeine and dopamine neurotransmission...
  99. doi Repeated administration of a dopamine D1 receptor agonist reverses the increased proportions of striatal dopamine D1High and D2High receptors in methamphetamine-sensitized rats
    Takahide Shuto
    Department of Pharmacology, Kurume University School of Medicine, 67 Asahi Machi, Kurume, Fukuoka 830 0011, Japan
    Eur J Neurosci 27:2551-7. 2008
    ..The findings reveal postsynaptic mechanisms for the development of behavioural sensitization to MAP and the reversal of established sensitization by repeated administration of the dopamine D1 receptor agonist...
  100. ncbi Dopamine beta-hydroxylase knockout mice have alterations in dopamine signaling and are hypersensitive to cocaine
    Jesse R Schank
    Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
    Neuropsychopharmacology 31:2221-30. 2006
    ....

Research Grants12

  1. RECEPTORS MEDIATING DRUG DEPENDENCE
    Philip Seeman; Fiscal Year: 1999
    ....
  2. RECEPTORS FOR COCAINE AND DOPAMINE
    Philip Seeman; Fiscal Year: 1993
    ..The availability of clones for these receptors would facilitate new drug design and provide new markers for disease linkage studies in families...