title: Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: increased dopamine D2 receptor dimerization.
abstract: BACKGROUND
  All antipsychotics work via dopamine D2 receptors (D2Rs), suggesting a critical role for D2Rs in psychosis; however, there is little evidence for a change in receptor number or pharmacological nature of D2Rs. Recent data suggest that D2Rs form dimers in-vitro and in-vivo, and we hypothesized that schizophrenia, as well as preclinical models of schizophrenia, would demonstrate altered dimerization of D2Rs, even though the overall number of D2Rs was unaltered.
  
  
  METHODS
  We measured the expression of D2Rs dimers and monomers in patients with schizophrenia using Western blots, and then in striatal tissue from rats exhibiting the amphetamine-induced sensitized state (AISS). We further examined the interaction between D2Rs and the dopamine transporter (DAT) by co-immunoprecipitation, and measured the expression of dopamine D2High receptors with ligand binding assays in rat striatum slices with or without acute amphetamine pre-treatment.
  
  
  RESULTS
  We observed significantly enhanced expression of D2Rs dimers (277.7 ± 33.6%) and decreased expression of D2Rs monomers in post-mortem striatal tissue of schizophrenia patients. We found that amphetamine facilitated D2Rs dimerization in both the striatum of AISS rats and in rat striatal neurons. Furthermore, amphetamine-induced D2Rs dimerization may be associated with the D2R-DAT protein-protein interaction as an interfering peptide that disrupts the D2R-DAT coupling, blocked amphetamine-induced up-regulation of D2Rs dimerization.
  
  
  CONCLUSIONS
  Given the fact that amphetamine induces psychosis and that the AISS rat is a widely accepted animal model of psychosis, our data suggest that D2R dimerization may be important in the pathophysiology of schizophrenia and may be a promising new target for novel antipsychotic drugs.
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Pei
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fletcher
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
authors.forename: Philip
authors.initials: P
authors.lastname: Seeman
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
mesh_terms: D000368:Aged; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D006801:Humans; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011180:Postmortem Changes; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000737:chemistry* / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; D000661:Amphetamine; D004298:Dopamine
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