期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：50
页码：E8178-E8186
DOI：10.1073/pnas.1614347113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceSchizophrenia is a debilitating psychiatric disorder characterized by positive, negative, and cognitive symptoms. Current antipsychotic drugs, including D2 receptor (D2R) partial agonist aripiprazole, antagonize excess striatal dopamine (DA) neurotransmission and reverse positive symptoms but are not efficacious at reversing cortical-related cognitive symptoms. Here, we show using pharmacological, behavioral, and electrophysiological approaches that a {beta}-arrestin2 ({beta}arr2)-biased D2R ligand has opposite antagonist and agonist actions in the striatum and cortex, respectively. This phenomenon is regulated by differential expression levels of signal transducer proteins G protein-coupled receptor kinase 2 and {beta}arr2. Thus, D2R-{beta}arr2-biased ligands have the potential to simultaneously target excess striatal and deficient cortical DA neurotransmission and provide more broadly effective therapies for schizophrenia. 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.
