title: Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain.
abstract: The dopamine hypothesis of schizophrenia posits that increased subcortical dopamine underpins psychosis. In vivo imaging studies indicate an increased presynaptic dopamine synthesis capacity in striatal terminals and cell bodies in the midbrain in schizophrenia; however, measures of the dopamine-synthesising enzyme, tyrosine hydroxylase (TH), have not identified consistent changes. We hypothesise that dopamine dysregulation in schizophrenia could result from changes in expression of dopamine synthesis enzymes, receptors, transporters or catabolic enzymes. Gene expression of 12 dopamine-related molecules was examined in post-mortem midbrain (28 antipsychotic-treated schizophrenia cases/29 controls) using quantitative PCR. TH and the synaptic dopamine transporter (DAT) proteins were examined in post-mortem midbrain (26 antipsychotic-treated schizophrenia cases per 27 controls) using immunoblotting. TH and aromatic acid decarboxylase (AADC) mRNA and TH protein were unchanged in the midbrain in schizophrenia compared with controls. Dopamine receptor D2 short, vesicular monoamine transporter (VMAT2) and DAT mRNAs were significantly decreased in schizophrenia, with no change in DRD3 mRNA, DRD3nf mRNA and DAT protein between diagnostic groups. However, DAT protein was significantly increased in putatively treatment-resistant cases of schizophrenia compared to putatively treatment-responsive cases. Midbrain monoamine oxidase A (MAOA) mRNA was increased, whereas MAOB and catechol-O-methyl transferase mRNAs were unchanged in schizophrenia. We conclude that, whereas some mRNA changes are consistent with increased dopamine action (decreased DAT mRNA), others suggest reduced dopamine action (increased MAOA mRNA) in the midbrain in schizophrenia. Here, we identify a molecular signature of dopamine dysregulation in the midbrain in schizophrenia that mainly includes gene expression changes of molecules involved in dopamine synthesis and in regulating the time course of dopamine action.
authors.affiliation: Schizophrenia Research Institute, Sydney, NSW, Australia.|Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, NSW, Australia.|School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
authors.forename: T D
authors.initials: TD
authors.lastname: Purves-Tyson
authors.affiliation: Schizophrenia Research Institute, Sydney, NSW, Australia.|Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, NSW, Australia.|School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
authors.forename: S J
authors.initials: SJ
authors.lastname: Owens
authors.affiliation: Schizophrenia Research Institute, Sydney, NSW, Australia.|Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, NSW, Australia.
authors.forename: D A
authors.initials: DA
authors.lastname: Rothmond
authors.affiliation: Ageing and Neurodegeneration, Neuroscience Research Australia, Sydney, NSW, Australia.|School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
authors.forename: G M
authors.initials: GM
authors.lastname: Halliday
authors.affiliation: Discipline of Biomedical Science and Brain and Mind Centre, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: K L
authors.initials: KL
authors.lastname: Double
authors.affiliation: Schizophrenia Research Institute, Sydney, NSW, Australia.|New South Wales Brain Tissue Resource Centre, Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Stevens
authors.affiliation: New South Wales Brain Tissue Resource Centre, Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: T
authors.initials: T
authors.lastname: McCrossin
authors.affiliation: Schizophrenia Research Institute, Sydney, NSW, Australia.|Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, NSW, Australia.|School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Shannon Weickert
mesh_terms: D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001344:Autopsy; D015153:Blotting, Western; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000378:metabolism*; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000235:genetics; D017072:Neostriatum / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017729:Presynaptic Terminals / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; C493593:DRD3 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D050637:Receptors, Dopamine D3; C493452:SLC18A2 protein, human; D050493:Vesicular Monoamine Transport Proteins; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D004298:Dopamine