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

被引:59
作者
Park, Su M. [1 ]
Chen, Meng [1 ]
Schmerberg, Claire M. [1 ]
Dulman, Russell S. [1 ]
Rodriguiz, Ramona M. [1 ,2 ]
Caron, Marc G. [3 ]
Jin, Jian [4 ,5 ,6 ]
Wetsel, William C. [1 ,2 ,3 ,7 ]
机构
[1] Duke Univ, Dept Psychiat & Behav Sci, Med Ctr, Durham, NC 27705 USA
[2] Duke Univ, Mouse Behav & Neuroendocrine Anal Core Facil, Med Ctr, Durham, NC 27705 USA
[3] Duke Univ, Dept Cell Biol, Med Ctr, Durham, NC 27705 USA
[4] Icahn Sch Med Mt Sinai, Dept Struct & Chem Biol, New York, NY 10029 USA
[5] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA
[6] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA
[7] Duke Univ, Dept Neurobiol, Med Ctr, Durham, NC 27705 USA
关键词
KNOCK-OUT MICE; ANTIPSYCHOTIC-DRUGS; GENETIC MODEL; FUNCTIONAL SELECTIVITY; PREPULSE INHIBITION; SIGNALING PATHWAY; HYPOFUNCTION; HALOPERIDOL; EFFICACY; DEFICITS;
D O I
10.1038/npp.2015.196
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 beta-arrestin-(beta Arr)-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/beta Arr 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.
引用
收藏
页码:704 / 715
页数:12
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