@article{c1225a596401456ba47657afc614622b,
title = "Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties",
abstract = "The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripipra-zole, 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 hyperand 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 proteincoupled 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.",
keywords = "Antipsychotics, Arrestin, Biased signaling, Dopamine D2R, Fast-spiking interneurons",
author = "Urs, {Nikhil M.} and Gee, {Steven M.} and Pack, {Thomas F.} and McCorvy, {John D.} and Tama Evron and Snyder, {Joshua C.} and Xiaobao Yang and Rodriguiz, {Ramona M.} and Emiliana Borrelli and Wetsel, {William C.} and Jian Jin and Roth, {Bryan L.} and Patricio O'Donnell and Caron, {Marc G.} and Snyder, {Solomon H.}",
note = "Funding Information: We thank Xiuqin Zhang and Benjamin Phillips for maintenance of the mouse colony. Antibodies to βarr2 for Western blot analyses (A2CT) and βarr2-specific IHC antibody were generous gifts from Dr. Robert Lefkowitz (Duke University) and Dr. Jeff Benovic (Thomas Jefferson University), respectively. Human postmortem brain samples were obtained from Dr. Craig Stockmeier (Postmortem Brain Core, University of Mississippi Medical Center). We also acknowledge the assistance of Dr. James C. Overholser, Dr. George Jurjus, and Lesa Dieter in psychiatric assessments and Gouri Mahajan in tissue preparation. This work was supported, in part, by NIH Grants 5R37-MH-073853 and 5U-19-MH-082441. Support from the Sidney R. Baer Jr. Foundation (N.M.U.) and the Pall Family Foundation (M.G.C.) for parts of this work is also greatly appreciated. This study was also supported by an award from the Ruth K. Broad Biomedical Research Foundation (T.F.P.) and the National Cancer Institute (NCI) Clinical Oncology Research Career Development Program NCI 5K12-CA100639-10 (to J.C.S.). Some of the behavioral experiments were conducted with equipment and software purchased with a North Carolina Biotechnology Center grant. The Postmortem Brain core is supported by Institutional Development Award (IDeA) Centers of Biomedical Research Excellence (COBRE) Program of NIH/National Institute of General Medical Sciences Grant P30 GM103328. We acknowledge the support of the Cuyahoga County Medical Examiner's Office.",
year = "2016",
month = dec,
day = "13",
doi = "10.1073/pnas.1614347113",
language = "English (US)",
volume = "113",
pages = "E8178--E8186",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "50",
}