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 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.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Nikhil M
authors.initials: NM
authors.lastname: Urs
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer, Inc., Cambridge, MA 02139.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Gee
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Pack
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill Medical School, Chapel Hill, NC 27514.|Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill Medical School, Chapel Hill, NC 27514.|National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill Medical School, Chapel Hill, NC 27514.
authors.forename: John D
authors.initials: JD
authors.lastname: McCorvy
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Tama
authors.initials: T
authors.lastname: Evron
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Snyder
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Xiaobao
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710.
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, CA 92697.
authors.forename: Emiliana
authors.initials: E
authors.lastname: Borrelli
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.|Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710.|Department of Medicine and Neurobiology, Duke University Medical Center, Durham, NC 27710.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill Medical School, Chapel Hill, NC 27514.|Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill Medical School, Chapel Hill, NC 27514.|National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill Medical School, Chapel Hill, NC 27514.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer, Inc., Cambridge, MA 02139.
authors.forename: Patricio
authors.initials: P
authors.lastname: O'Donnell
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710; marc.caron@dm.duke.edu.|Department of Medicine and Neurobiology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007395:Interneurons / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010622:Phencyclidine / Q000633:toxicity; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071560:beta-Arrestin 2 / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; C000600618:DRD2 protein, mouse; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D017448:Receptors, Dopamine D2; D000071560:beta-Arrestin 2; C496567:GRK2 protein, human; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D019204:GTP-Binding Proteins; D010622:Phencyclidine
keywords: antipsychotics; arrestin; biased signaling; dopamine D2R; fast-spiking interneurons