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State-Dependent Dopamine System Regulation Using Current and Novel Antipsychotic Drug Mechanisms: Developmental Implications in a Schizophrenia Model

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State-Dependent Dopamine System Regulation Using Current and Novel Antipsychotic Drug Mechanisms: Developmental Implications in a Schizophrenia Model Title Page STATE-DEPENDENT DOPAMINE SYSTEM REGULATION USING CURRENT AND NOVEL ANTIPSYCHOTIC DRUG MECHANISMS: DEVELOPMENTAL IMPLICATIONS IN A SCHIZOPHRENIA MODEL by Susan Franklin Sonnenschein B.S., Psychology and Neuroscience, Michigan State University, 2014 Submitted to the Graduate Faculty of the Dietrich School of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2020 Committee Page UNIVERSITY OF PITTSBURGH DIETRICH SCHOOL OF ARTS AND SCIENCES This dissertation was presented by Susan Franklin Sonnenschein It was defended on December 19, 2019 and approved by Anissa Abi-Dargham, MD, Department of Psychiatry, Stony Brook University Beatriz Luna, PhD, Department of Psychiatry Robert Turner, PhD,, Department of Neurobiology David Volk, MD, PhD, Department of Psychiatry Dissertation Advisor: Anthony Grace, PhD, Department of Neuroscience Dissertation Chair: Susan Sesack, PhD, Department of Neuroscience ii Copyright © by Susan Franklin Sonnenschein 2020 iii STATE-DEPENDENT DOPAMINE SYSTEM REGULATION USING CURRENT AND NOVEL ANTIPSYCHOTIC DRUG MECHANISMS: DEVELOPMENTAL IMPLICATIONS IN A SCHIZOPHRENIA MODEL Susan Franklin Sonnenschein PhD University of Pittsburgh, 2020 Current antipsychotic drugs act on dopamine (DA) D2 receptors for their therapeutic effects, but their limitations have driven a search for novel treatments. Pharmaceutical research is generally performed in normal rats, whereas models that account for variables including disease- relevant pathophysiology may improve predictive validity. D2 antagonists have been shown to reduce DA neuron activity via D2 autoreceptors to produce over-excitation induced cessation of cell firing (depolarization block). Aripiprazole is a D2 partial agonist shown to normalize hypodopaminergic and hyperdopaminergic states, but through unclear mechanisms. The methylazoxymethanol acetate (MAM) model was used to observe aripiprazole’s effects on hyperdopaminergic activity, compared to control (SAL) rats, using in vivo, anesthetized, electrophysiological recordings. Aripiprazole had no effect in controls, but reduced hyperdopaminergic activity in MAM rats, which was not reversed by apomorphine, suggesting a mechanism other than depolarization block. Furthermore, aripiprazole removed D2 antagonist- induced depolarization block in MAM rats, consistent with autoreceptor agonism, potentially explaining its downregulation of hyperdopaminenrgic activity. These results demonstrate state- dependent neuropharmacological effects. Group II metabotropic glutamate receptors (mGluR2/3) showed promise as a novel target in preclinical research, but the mGluR2/3 agonist, pomaglumetad methionil (POM), showed insufficient efficacy in clinical trials. Although previous studies have shown that mGluR2/3 agonists have no effect on DA in normal rats, MAM rats were used to iv determine whether POM normalizes a hyperdopaminergic state. POM dose-dependently reduced DA neuron activity of MAM rats, not observed in SAL rats. Intra-ventral hippocampal (vHPC) infusion of POM was sufficient to reduce dopaminergic activity in MAM rats. POM also increased novel object recognition in MAM rats and blocked stress-induced increases in dopaminergic activity in normal rats. To examine developmental effects of POM on MAM, MAM and SAL rats were treated peripubertally and DA neuron activity and vHPC pyramidal neuron activity were recorded in early or late adulthood. POM-treated MAM rats demonstrated normalized DA neuron activity and vHPC pyramidal neuron activity at both timepoints. Thus, POM indirectly regulates DA neuron activity by reducing increased vHPC activity and can prevent DA system hyperactivity in adult MAM rats following peripubertal administration. v TABLE OF CONTENTS TITLE PAGE ................................................................................................................................. i COMMITTEE PAGE ................................................................................................................... ii TABLE OF CONTENTS ............................................................................................................ vi LIST OF FIGURES .......................................................................................................................x LIST OF ABBREVIATIONS .................................................................................................... xii PREFACE ................................................................................................................................... xiv ACKNOWLEDGEMENTS ........................................................................................................xv 1.0 GENERAL INTRODUCTION ...............................................................................................1 1.1 PATHOPHYSIOLOGY OF SCHIZOPHRENIA ....................................................... 1 1.1.1 Schizophrenia Within a Systems Neuroscience Perspective of Psychiatric Disorders ........................................................................................................................1 1.1.2 Dopamine Dysfunction in Schizophrenia ...........................................................3 1.1.3 Hippocampal Dysfunction in Schizophrenia .....................................................5 1.1.4 The Development of DA Dysfunction via Hippocampal Dysfunction: Insights from Animal Models .....................................................................................................6 1.1.5 Dopamine Dysfunction within an Aberrant Salience Framework ................10 1.2 TREATMENTS FOR PSYCHOSIS IN SCHIZOPHRENIA ................................... 12 1.2.1 Current Treatments for Schizophrenia ...........................................................12 1.2.2 Limitations of Current Antipsychotic Drugs ...................................................16 1.2.3 Novel Antipsychotic Mechanisms .....................................................................18 1.2.4 Stage Specific Treatments .................................................................................19 vi 1.3 PURPOSE OF STUDIES ............................................................................................. 20 1.3.1 Rationale .............................................................................................................20 1.3.2 Hypothesis and Research Objectives ................................................................22 2.0 STATE-DEPENDENT EFFECTS OF D2 PARTIAL AGONIST ARIPIPRAZOLE ON DOPAMINE NEURON ACTIVITY IN THE MAM MODEL OF SCHIZOPHRENIA ......28 2.1 INTRODUCTION ........................................................................................................ 28 2.2 METHODS .................................................................................................................... 30 2.3 RESULTS ...................................................................................................................... 34 2.3.1 Acute Aripiprazole Administration Reduces VTA DA Neuron Activity of MAM but Not SAL Rats .............................................................................................34 2.3.2 Repeated Aripiprazole Administration Reduces VTA DA Neuron Activity of MAM but Not SAL Rats .............................................................................................35 2.3.3 Persistent Reduction of VTA DA Neuron Activity Following Withdrawal From Repeated Aripiprazole Administration ..........................................................36 2.3.4 Acute Aripiprazole Administration Reverses Haloperidol-Induced Depolarization Block in MAM Rats ..........................................................................38 2.4 DISCUSSION ................................................................................................................ 43 3.0 THE MGLUR2/3 AGONIST POMAGLUMETAD METHIONIL INDIRECTLY REGULATES DOPAMINE NEURON ACTIVITY VIA ACTION IN THE VENTRAL HIPPOCAMPUS ..........................................................................................................................50 3.1 INTRODUCTION ........................................................................................................ 50 3.2 METHODS .................................................................................................................... 52 3.3 RESULTS ...................................................................................................................... 57 vii 3.3.1 Pomaglumetad Dose-Dependently Reduces DA Neuron Activity in MAM Rats ...............................................................................................................................57 3.3.2 Intra-Ventral Hippocampal Infusion of Pomaglumetad is Sufficient to Reduce DA Neuron Activity in MAM Rats ..............................................................59 3.3.3 Pomaglumetad Increases Novel Object Recognition in MAM Rats ..............59 3.3.4 Pomaglumetad Blocks Restraint Stress-Induced Increase in DA Neuron Activity .........................................................................................................................60 3.4 DISCUSSION ................................................................................................................ 64 4.0 PERIPUBERTAL TREATMENT WITH MGLUR2/3 AGONIST PREVENTS DOPAMINE SYSTEM HYPERACTIVITY IN ADULTHOOD IN THE MAM MODEL OF SCHIZOPHRENIA......................................................................................................................69
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