Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties

Nikhil M. Urs, Steven M. Gee, Thomas F. Pack, John D. McCorvy, Tama Evron, Joshua C. Snyder, Xiaobao Yang, Ramona M. Rodriguiz, Emiliana Borrelli, William C. Wetsel, Jian Jin, Bryan L. Roth, Patricio O'Donnell, Marc G. Caron, Solomon H. Snyder

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)E8178-E8186
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number50
DOIs
StatePublished - Dec 13 2016

Keywords

  • Antipsychotics
  • Arrestin
  • Biased signaling
  • Dopamine D2R
  • Fast-spiking interneurons

ASJC Scopus subject areas

  • General

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    Urs, N. M., Gee, S. M., Pack, T. F., McCorvy, J. D., Evron, T., Snyder, J. C., Yang, X., Rodriguiz, R. M., Borrelli, E., Wetsel, W. C., Jin, J., Roth, B. L., O'Donnell, P., Caron, M. G., & Snyder, S. H. (2016). Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. Proceedings of the National Academy of Sciences of the United States of America, 113(50), E8178-E8186. https://doi.org/10.1073/pnas.1614347113