| First Author | Urs NM | Year | 2016 |
| Journal | Proc Natl Acad Sci U S A | Volume | 113 |
| Issue | 50 | Pages | E8178-E8186 |
| PubMed ID | 27911814 | Mgi Jnum | J:247440 |
| Mgi Id | MGI:5926012 | Doi | 10.1073/pnas.1614347113 |
| Citation | Urs NM, et al. (2016) Distinct cortical and striatal actions of a beta-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. Proc Natl Acad Sci U S A 113(50):E8178-E8186 |
| abstractText | The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed beta-arrestin2 (betaarr2)-biased D2R partial agonists to simultaneously target hyper- and hypodopaminergia. Using neuron-specific betaarr2-KO mice, we show that the antipsychotic-like effects of a betaarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-betaarr2 signaling. Furthermore, betaarr2-biased D2R agonism enhances firing of cortical fast-spiking interneurons. This enhanced cortical agonism of the biased ligand can be attributed to a lack of G-protein signaling and elevated expression of betaarr2 and G protein-coupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that betaarr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies. |
