TY - JOUR
T1 - Effects of β-Arrestin-Biased Dopamine D2 Receptor Ligands on Schizophrenia-Like Behavior in Hypoglutamatergic Mice
AU - Park, Su M.
AU - Chen, Meng
AU - Schmerberg, Claire M.
AU - Dulman, Russell S.
AU - Rodriguiz, Ramona M.
AU - Caron, Marc G.
AU - Jin, Jian
AU - Wetsel, William C.
N1 - Funding Information:
We thank Theodore Rhodes, Zayd Ahmed, Christopher Means, Paul Skiba, and Brittany Thompson for assisting with some of the behavioral testing and Ms Jiechun Zhou for genotyping and maintaining the mice. Some of the behavioral experiments were conducted with equipment and software purchased with a North Carolina Biotechnology Center grant. We obtained the βArr2 mice from Dr Laura Bohn (Scripps Research Institute, Juniper, FL) and they were further backcrossed with C57BL/6J mice. We also received the NR1 mice from Dr Amy J Ramsey (University of Toronto, Ontario, Canada) and they were further backcrossed to C57BL/6 and 129 mice as separate lines. This work was supported by the NIMH grant U19-MH082441. Drs Caron, Jin, and Wetsel received NIH funding.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84954027637&partnerID=8YFLogxK
U2 - 10.1038/npp.2015.196
DO - 10.1038/npp.2015.196
M3 - Article
C2 - 26129680
AN - SCOPUS:84954027637
VL - 41
SP - 704
EP - 715
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 3
ER -