Distinct Cortical And Striatal Actions Of A Beta-Arrestin-Biased Dopamine D2 Receptor Ligand Reveal Unique Antipsychotic-Like Properties

The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed beta-arrestin2 (beta arr2)-biased D2R partial agonists to simultaneously target hyper-and hypodopaminergia. Using neuron-specific beta arr2-KO mice, we show that the antipsychotic-like effects of a beta arr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-beta arr2 signaling. Furthermore, beta arr2-biased D2R agonism enhances firing of cortical fast-spiking interneurons. This enhanced cortical agonism of the biased ligand can be attributed to a lack of G-protein signaling and elevated expression of beta arr2 and G protein-coupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that beta arr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies.