Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):E8178-E8186. Epub 2016 Dec 1.

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

Author information

1
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
2
Neuroscience and Pain Research Unit, Pfizer, Inc., Cambridge, MA 02139.
3
Department of Pharmacology, University of North Carolina at Chapel Hill Medical School, Chapel Hill, NC 27514.
4
Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill Medical School, Chapel Hill, NC 27514.
5
National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill Medical School, Chapel Hill, NC 27514.
6
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
7
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
8
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
9
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710.
10
Department of Microbiology and Molecular Genetics, University of California, Irvine, CA 92697.
11
Department of Medicine and Neurobiology, Duke University Medical Center, Durham, NC 27710.
12
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710; marc.caron@dm.duke.edu.

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.

KEYWORDS:

antipsychotics; arrestin; biased signaling; dopamine D2R; fast-spiking interneurons

PMID:
27911814
PMCID:
PMC5167191
DOI:
10.1073/pnas.1614347113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

P.O. is an employee and shareholder at Pfizer, Inc. M.G.C. has received compensation from Lundbeck as a member of their Psychopharmacology Advisory Board and is a consultant for Omeros Corp. M.G.C. also owns equity in Acadia Pharmaceuticals.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center