Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: increased dopamine D2 receptor dimerization
AuthorWang, M; Pei, L; Fletcher, PJ; Kapur, S; Seeman, P; Liu, F
Source TitleMolecular Brain
University of Melbourne Author/sKapur, Shitij
AffiliationMedicine Dentistry & Health Sciences
Document TypeJournal Article
CitationsWang, M., Pei, L., Fletcher, P. J., Kapur, S., Seeman, P. & Liu, F. (2010). Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: increased dopamine D2 receptor dimerization. MOLECULAR BRAIN, 3 (1), https://doi.org/10.1186/1756-6606-3-25.
Access StatusOpen Access
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.
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