Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. Proc Natl Acad Sci U S A 2016 Dec 13;113(50):E8178-E8186
Date
12/03/2016Pubmed ID
27911814Pubmed Central ID
PMC5167191DOI
10.1073/pnas.1614347113Scopus ID
2-s2.0-85005965121 (requires institutional sign-in at Scopus site) 127 CitationsAbstract
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.
Author List
Urs NM, Gee SM, Pack TF, McCorvy JD, Evron T, Snyder JC, Yang X, Rodriguiz RM, Borrelli E, Wetsel WC, Jin J, Roth BL, O'Donnell P, Caron MGAuthor
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntipsychotic Agents
Behavior, Animal
Cerebral Cortex
Corpus Striatum
Dopamine D2 Receptor Antagonists
Female
G-Protein-Coupled Receptor Kinase 2
GTP-Binding Proteins
HEK293 Cells
Humans
Interneurons
Ligands
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Phencyclidine
Receptors, Dopamine D2
Signal Transduction
beta-Arrestin 2
