title: Reduced insulin-receptor mediated modulation of striatal dopamine release by basal insulin as a possible contributing factor to hyperdopaminergia in schizophrenia.
abstract: Schizophrenia is a severe and chronic neuropsychiatric disorder which affects 1% of the world population. Using the brain imaging technique positron emission tomography (PET) it has been demonstrated that persons with schizophrenia have greater dopamine transmission in the striatum compared to healthy controls. However, little progress has been made as to elucidating other biological mechanisms which may account for this hyperdopaminergic state in this disease. Studies in animals have demonstrated that insulin receptors are expressed on midbrain dopamine neurons, and that insulin from the periphery acts on these receptors to modify dopamine transmission in the striatum. This is pertinent given that several lines of evidence suggest that insulin receptor functioning may be abnormal in the brains of persons with schizophrenia. Post-mortem studies have shown that persons with schizophrenia have less than half the number of cortical insulin receptors compared to healthy persons. Moreover, these post-mortem findings are unlikely due to the effects of antipsychotic treatment; studies in cell lines and animals suggest antipsychotics enhance insulin receptor functioning. Further, hyperinsulinemia - even prior to antipsychotic use - seems to be related to less psychotic symptoms in patients with schizophrenia. Collectively, these data suggest that midbrain insulin receptor functioning may be abnormal in persons with schizophrenia, resulting in reduced insulin-mediated regulation of dopamine transmission in the striatum. Such a deficit may account for the hyperdopaminergic state observed in these patients and would help guide the development of novel treatment strategies. We hypothesize that, (i) insulin receptor expression and/or function is reduced in midbrain dopamine neurons in persons with schizophrenia, (ii) basal insulin should reduce dopaminergic transmission in the striatum via these receptors, and (iii) this modulation of dopaminergic transmission by basal insulin is reduced in the brains of persons with schizophrenia.
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada; Institute of Medical Science, University of Toronto, 2374 Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Fernando
authors.initials: F
authors.lastname: Caravaggio
authors.affiliation: Institute of Medical Science, University of Toronto, 2374 Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario M5T 1R8, Canada.
authors.forename: Margaret
authors.initials: M
authors.lastname: Hahn
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada; Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario M5T 1R8, Canada.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada; Institute of Medical Science, University of Toronto, 2374 Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario M5T 1R8, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Gerretsen
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada; Institute of Medical Science, University of Toronto, 2374 Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario M5T 1R8, Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Remington
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada; Institute of Medical Science, University of Toronto, 2374 Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario M5T 1R8, Canada. Electronic address: ariel.graff@camh.ca.
authors.forename: Ariel
authors.initials: A
authors.lastname: Graff-Guerrero
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D015897:Comorbidity; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008962:Models, Theoretical; D009474:Neurons / Q000378:metabolism; D049268:Positron-Emission Tomography; D011972:Receptor, Insulin / Q000378:metabolism / Q000502:physiology*; D012559:Schizophrenia / Q000150:complications / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D014150:Antipsychotic Agents; D007328:Insulin; C435941:INSR protein, human; D011972:Receptor, Insulin; D004298:Dopamine