RGD Reference Report - Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: increased dopamine D2 receptor dimerization. - Rat Genome Database

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Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: increased dopamine D2 receptor dimerization.

Authors: Wang, M  Pei, L  Fletcher, PJ  Kapur, S  Seeman, P  Liu, F 
Citation: Wang M, etal., Mol Brain. 2010 Sep 2;3:25.
RGD ID: 6907450
Pubmed: PMID:20813060   (View Abstract at PubMed)
PMCID: PMC2942879   (View Article at PubMed Central)
DOI: DOI:10.1186/1756-6606-3-25   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
schizophrenia  IEP 6907450protein:increase homodimerization:striatumRGD 
schizophrenia  ISODRD2 (Homo sapiens)6907450; 6907450protein:increase homodimerization:striatumRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
identical protein binding  IPIDrd2 (Rattus norvegicus)6907450homodimerizationRGD 

Objects Annotated

Genes (Rattus norvegicus)
Drd2  (dopamine receptor D2)

Genes (Mus musculus)
Drd2  (dopamine receptor D2)

Genes (Homo sapiens)
DRD2  (dopamine receptor D2)


Additional Information