PM435. Targeting Functional Selectivity of the Dopamine D2 Receptor for Treatment of Schizophrenia-like Behaviors
Year: 2016
Type: conference-abstract
Abstract: Ligand binding can lead to conformational changes in G protein-coupled receptors (GPCRs) that produce differential signaling events. These alterations can activate, inhibit, or exert no effects on the G protein-dependent signaling pathway while producing similar or diverse actions on the G protein-independent pathway through β-arrestin (βArr). This property of functional selectivity is novel and all approved drugs by the US Federal Drug Administration were not developed with this characteristic in mind. All current antipsychotic drugs bind to the dopamine D2 receptor (D2R). The purpose of our studies was to determine whether several βArr-biased compounds would show efficacy in two separate mouse genetic models of schizophrenia-like behaviors. The hypoglutamatergic NR1 knockdown (KD) and the hyperdopaminergic dopamine transporter knockout (DAT-KO) mice were subjected to behavioral tests for positive, negative, and cognitive schizophrenia-like responses. The D2R βArr-biased compounds, UNC9994 and UNC9975, were found to reduce hyperlocomotion in both NR1-KD and DAT-KO mice, whereas the compounds were only efficacious in normalizing prepulse inhibition in NR1-KD mice. The compounds also restored social behavior and novel object recognition memory in the two strains of mice. Using vesicular monoamine transporter 2 heterozygotes as a model for depressive-like behaviors, we observed that the UNC9995 decreased immobility in the tail suspension task to levels of the wild-type controls. Compared to haloperidol, catalepsy was very low with the UNC compounds. In summary, both βArr-biased compounds demonstrated efficacy in alleviating schizophrenia-like responses in the presistently hypoglutamatergic NR1-KD and the hyperdopaminergic DAT-KO mice. Together, these results suggest that βArr-bias may represent a unique approach for developing D2R drugs to treat schizophrenia and other related disorders in human patients. Supported by U19MH82441
Institutions: Duke Medical Center, Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,693
OpenAlex ID: W2891483985