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Distinct cortical and striatal actions of a β-arrestin–biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties
- Source :
- Proceedings of the National Academy of Sciences. 113
- Publication Year :
- 2016
- Publisher :
- Proceedings of the National Academy of Sciences, 2016.
-
Abstract
- 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 β-arrestin2 (βarr2)-biased D2R partial agonists to simultaneously target hyper- and hypodopaminergia. Using neuron-specific βarr2-KO mice, we show that the antipsychotic-like effects of a βarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-βarr2 signaling. Furthermore, βarr2-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 βarr2 and G protein-coupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that βarr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies.
- Subjects :
- Male
0301 basic medicine
Mice, 129 Strain
G-Protein-Coupled Receptor Kinase 2
Phencyclidine
Biology
Ligands
Partial agonist
Mice
03 medical and health sciences
0302 clinical medicine
GTP-Binding Proteins
Interneurons
Dopamine
Dopamine receptor D2
medicine
Arrestin
Animals
Humans
Receptor
G protein-coupled receptor
Cerebral Cortex
Mice, Knockout
Multidisciplinary
Behavior, Animal
Receptors, Dopamine D2
beta-Arrestin 2
Corpus Striatum
Mice, Inbred C57BL
Dopamine D2 Receptor Antagonists
HEK293 Cells
030104 developmental biology
medicine.anatomical_structure
PNAS Plus
Cerebral cortex
Female
Signal transduction
Neuroscience
030217 neurology & neurosurgery
Antipsychotic Agents
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 113
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....fafd1936b210fea05ce3361413fa361f