Abstract
BackgroundAll 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.MethodsWe 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.ResultsWe 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.ConclusionsGiven 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.
Highlights
All antipsychotics work via dopamine D2 receptors (D2Rs), suggesting a critical role for D2Rs in psychosis; there is little evidence for a change in receptor number or pharmacological nature of D2Rs
We started with analysis of postmortem striatal sections from schizophrenia patients and observed a significant increase in D2R dimers at the expense of monomers. To examine if this pathology was observed in preclinical models of schizophrenia that involve a hyper-dopaminergic state, we examined the status of D2R dimers in rats exhibiting an amphetamine-induced sensitized state (AISS)
Enhanced expression of D2R dimers in postmortem striatal sections from schizophrenia patients As an initial step to investigate whether the expression pattern of D2R might be altered in schizophrenia, we carried out Western blot analysis with all 60 formalinfixed paraffin-embedded human postmortem striatal sections from the Stanley Foundation, including 15 samples from each of four groups: control, bipolar disorder (BD), major depressive disorder (MDD) and schizophrenia (SZ)
Summary
All antipsychotics work via dopamine D2 receptors (D2Rs), suggesting a critical role for D2Rs in psychosis; there is little evidence for a change in receptor number or pharmacological nature of D2Rs. Most previous studies have measured D2R using receptor radioactive ligand binding assay, PET imaging or Western blot analysis. These techniques provide a good index of overall binding sites, but do not provide any insight into molecular aspects of receptor functions, including their potential configurations with other receptors. Dimerization of GPCRs may alter pharmacological properties and signaling transduction, leading to significant effects on cellular physiology as well as disease pathologies. Receptor hetero-dimerization makes it possible to modulate one receptor using ligands targeting the other receptor [7,8,9] These unique properties of receptor oligomerization have made them novel targets for the development of novel drugs [10]
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