Research
Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: increased dopamine D2 receptor dimerization
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* Corresponding author: Fang Liu f.liu.a@utoronto.ca
1 Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8, Canada
2 Institute of Psychiatry, University of London, London, SE5 8AF, UK
3 Department of Psychology, University of Toronto, Ontario M5S 3GS, Canada
4 Department of Psychiatry, University of Toronto, Ontario, M5T 1R8, Canada
5 Department of Pharmacology and Toxicology, University of Toronto, Ontario, M5S 1A8, Canada
6 Department of Neuroscience, Centre for Addiction and Mental Health, Clarke Division, 250 College Street, Toronto, Ontario M5T 1R8, Canada
Molecular Brain 2010, 3:25 doi:10.1186/1756-6606-3-25
Published: 2 September 2010Abstract
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.