Effects of β-Arrestin-Biased Dopamine D2 Receptor Ligands on Schizophrenia-Like Behavior in Hypoglutamatergic Mice

Su M. Park, Meng Chen, Claire M. Schmerberg, Russell S. Dulman, Ramona M. Rodriguiz, Marc G. Caron, Jian Jin, William C. Wetsel

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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.

Original languageEnglish
Pages (from-to)704-715
Number of pages12
JournalNeuropsychopharmacology
Volume41
Issue number3
DOIs
StatePublished - 1 Feb 2016

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