title: Effects of β-Arrestin-Biased Dopamine D2 Receptor Ligands on Schizophrenia-Like Behavior in Hypoglutamatergic Mice.
abstract: Current antipsychotic drugs (APDs) show efficacy with positive symptoms, but are limited in treating negative or cognitive features of schizophrenia. Whereas all currently FDA-approved medications target primarily the dopamine D2 receptor (D2R) to inhibit G(i/o)-mediated adenylyl cyclase, a recent study has shown that many APDs affect not only G(i/o)- but they can also influence β-arrestin- (βArr)-mediated signaling. The ability of ligands to differentially affect signaling through these pathways is termed functional selectivity. We have developed ligands that are devoid of D2R-mediated G(i/o) protein signaling, but are simultaneously partial agonists for D2R/βArr interactions. The purpose of this study was to test the effectiveness of UNC9975 or UNC9994 on schizophrenia-like behaviors in phencyclidine-treated or NR1-knockdown hypoglutamatergic mice. We have found the UNC compounds reduce hyperlocomotion in the open field, restore PPI, improve novel object recognition memory, partially normalize social behavior, decrease conditioned avoidance responding, and elicit a much lower level of catalepsy than haloperidol. These preclinical results suggest that exploitation of functional selectivity may provide unique opportunities to develop drugs with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related conditions than medications that are currently available.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
authors.forename: Su M
authors.initials: SM
authors.lastname: Park
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Schmerberg
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Dulman
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.|Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA.
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.affiliation: Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.|Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA.|Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.|Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002375:Catalepsy / Q000378:metabolism; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D057507:Mice, 129 Strain; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D010622:Phencyclidine; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency* / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D012565:Schizophrenic Psychology; D012919:Social Behavior; D000071557:beta-Arrestins
chemical_list: D014150:Antipsychotic Agents; D019390:Arrestins; C000600618:DRD2 protein, mouse; D015259:Dopamine Agents; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D000071557:beta-Arrestins; D018698:Glutamic Acid; D010622:Phencyclidine