Caron, Marc GKuhn, Cynthia MoretonPack, Thomas Franklin2018-05-312019-04-262018https://hdl.handle.net/10161/16905<p>Herein I describe studies I have undertaken that were aimed at understanding the mechanisms of achieving β-arrestin-biased signaling at the dopamine D2 receptor (D2R), methods for studying downstream mediators of β-arrestin-biased signaling, and the development of a mouse model of schizophrenia that could test the efficacy of β-arrestin-biased D2R ligands. Each of these studies will improve our understanding of how to better tailor drugs to treat schizophrenia. I have employed a wide variety of in vitro and in vivo methods ranging from bioluminescent resonance energy transfer (BRET) to adeno-associated viral delivery of neuronal actuators. Ultimately, I was able to demonstrate that the D2R can achieve β-arrestin biased signaling through its ability to directly recruit the G protein-coupled receptor kinase 2 (GRK2). Next, I developed a BRET-based approach to study interactions of GPCR-β-arrestin complexes and applied this to the D2R. Finally, I have laid the ground work for a mouse model of schizophrenia capable of generating dopamine circuit imbalances hypothesized to occur in schizophrenia as a means to test β-arrestin-biased D2R ligands.</p>PharmacologyNeurosciencesDissertation