Characterizing antipsychotic behavioral and corticostriatal neurophysiological effects to psychotomimetic challenge

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2022

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Abstract

Schizophrenia is marked by significant disruptions to dopaminergic signaling across the mesolimbic and mesocortical circuits. Antipsychotic drugs have been largely unsuccessfully treating cognitive symptoms that debilitate the schizophrenia patient population. Dopamine 2 Receptor (D2R)- βeta arrestin 2 (βarr2) biased signaling, independent of the canonical G protein signaling, has emerged as a potential mechanism for antipsychotic drugs to restore dopaminergic signaling and improve treatment resistant cognitive symptoms. In the following experiments, I described gene editing tools to systematically investigate D2R signaling in a region or cell specific manner. Next, I evaluated the behavioral effects of two functionally selective D2-like βarr2 biased ligands against psychotomimetic challenge from phencyclidine or amphetamine. Then I employed chemogenetics to perform synthetic pharmacology experiments e.g. studying the signaling cascade of a drug without using the drug, to discover how D2- R βarr2 signaling produces antipsychotic effects in the prefrontal cortex. Lastly, I characterized the neurophysiological changes induced by phencyclidine and a D2R βarr2 biased ligand within relevant brain regions in the meso -limbic and -cortical circuits. Our results determined antipsychotic like activity is 1) regulated by excitation-inhibitory balance maintained by cortical GABA interneurons 2) dependent on βarr2.

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Thomas, Gwenaëlle E. (2022). Characterizing antipsychotic behavioral and corticostriatal neurophysiological effects to psychotomimetic challenge. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/25800.

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