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Extrastriatal Gabaa Receptors As a Nondopaminergic Target In EXTRASTRIATAL GABAA RECEPTORS AS A NONDOPAMINERGIC TARGET IN THE TREATMENT OF MOTOR SYMPTOMS OF PARKINSON’S DISEASE AND LEVODOPA-INDUCED DYSKINESIA by ROBERT ASSINI A dissertation submitted to the Graduate School—Newark Rutgers, The State University of New Jersey in partial fulfillment of the requirements for the degree of Doctor of Philosophy Graduate Program in Behavioral and Neural Sciences written under the direction of Professor Elizabeth D. Abercrombie and approved by ____________________________ Collin J. Lobb, PhD ____________________________ James M. Tepper, PhD ____________________________ Pierre-Olivier Polack, PhD ____________________________ Tibor Koos, PhD ____________________________ Elizabeth D. Abercrombie, PhD ___________________________ Juan Mena-Segovia, PhD Newark, New Jersey October, 2019 ©2019 Robert Assini ALL RIGHTS RESERVED ABSTRACT OF THE DISSERTATION Extrastriatal GABAA receptors as a nondopaminergic target in the treatment of motor symptoms of Parkinson’s disease and levodopa-induced dyskinesia By Robert Assini Dissertation Director: Prof. Elizabeth D. Abercrombie Parkinson’s disease is a progressive neurodegenerative disorder resulting from the death of the dopaminergic nigrostriatal projection to the basal ganglia. Extrastriatal nuclei within this circuit have been shown to exhibit synchronous oscillatory activity entrained to excessive cortical beta oscillations following dopamine depletion. Zolpidem binds to GABAA receptors at the benzodiazepine site, potentiating inhibitory postsynaptic currents with selectivity for receptors expressing the α1 subunit. Coincidentally, the nuclei expressing the α1 subunit within the BG are also those that have been shown to have increased synchronous bursting activity in a dopamine-depleted state. We hypothesize that this differential expression of the α1 subunit indicates zolpidem-sensitive GABAA receptors may constitute a potential non-dopaminergic therapeutic intervention in the treatment of PD motor symptoms. The work described in this dissertation explores this possibility using behavioral neuropharmacology and analytical chemistry. ii Acknowledgments This dissertation is dedicated to my grandparents, Dolores and Eugene Billeci, who passed away during the completion of this work. I would also like to thank my family, friends, and colleagues for their support throughout. iii Preface A version of the work described in Chapter III has been published (Assini and Abercrombie, 2018, European Journal of Neuroscience). Currently, Chapters IV and V are in preparation. iv Table of Contents Abstract…………………………………………………………………………………..ii Acknowledgments……………………………………………………………………….iii Preface…………………………………………………………………………………....iv Table of contents………………………………………………………………………….v List of tables……………………………………………………………………………..xii List of illustrations……………………………………………………………………...xiii List of abbreviations……………………………………………………………………..xv Chapter I Introduction 1.1 Significance………………………………………………………....……..1 1.2 Overview of the introduction……………………………………………...1 1.3 Parkinson’s disease: Motor symptoms, pathophysiology, and translational models……………………………………………………………………..4 1.3.1 Parkinson’s disease…………………………………………………4 1.3.2 Pathophysiology of Parkinson’s disease in the basal ganglia……....6 1.3.3 Neurotoxin lesion models of Parkinson’s disease………………….9 1.3.4 Concordant electrophysiological evidence of extrastriatal hyperexcitation across species…………………………………….13 1.3.5 Insights from rodent rotational behavior…………………………..14 1.3.6 Summary…………………………………………………………..16 1.4 Levodopa-induced dyskinesia……………………………………………17 1.4.1 Dopamine replacement as a short-lived therapeutic intervention…17 1.4.2 Levodopa: Mechanism of action…………………………………..18 v 1.4.3 Dopamine receptor supersensitivity……………………………….19 1.4.4 Neurophysiological correlates of levodopa-induced dyskinesia…..20 1.4.5 Measuring levodopa-induced dyskinesia in rodent models of Parkinson’s disease…………………………………………...…...22 1.4.6 Summary…………………………………………………………..23 1.5 GABAA receptors as a potential therapeutic target………………………24 1.5.1 Interventions beyond the dopamine system……………………….24 1.5.2 Role of subunit composition in selective affinity to drugs………..25 1.5.3 GABAergic receptor distribution in the basal ganglia: Insights for therapeutic targeting?.......................................................................26 1.5.4 GABAergic changes in Parkinson’s disease………………………28 1.5.5 Enhancing inhibition to combat extrastriatal hyperexcitation?.......31 1.5.6 Summary…………………………………………………………..31 1.6 Zolpidem…………………………………………………………………32 1.6.1 Selectivity…………………………………………………………32 1.6.2 Actions within the basal ganglia…………………………………..33 1.6.3 Comparative pharmacokinetics……………………………………34 1.6.4 Zolpidem in the treatment of movement disorders………………..38 1.6.5 Case studies of efficacy in Parkinson’s disease…………………...39 1.6.6 Summary…………………………………………………………..40 1.7 Introducing the data chapters…………………………………………….41 Chapter II General Methods 2.1 Animals…………………………………………………………………..43 vi 2.2 Stereotaxic surgery……………………………………………………….43 2.2.1 Unilateral 6-hydroxydopamine treatment………………………..43 2.2.2 Microdialysis implant procedure………………………………...44 2.3 Behavioral testing………………………………………………………..45 2.3.1 Rotarod balance beam test……………………………………….45 2.3.1.1 Rotarod performance in intact rats………………………46 2.3.1.2 Rotarod performance in unilaterally dopamine-depleted Rats………………………………………………………46 2.3.2 Cylinder/Paw preference test…………………………………….47 2.3.3 Levodopa-induced behavioral asymmetry……………………….48 2.3.3.1 Levodopa dose-response…………………………………48 2.3.3.2 Effects of zolpidem on levodopa-induced behavioral asymmetry………………………………………………..49 2.3.3.3 Behavioral asymmetry scoring system (BASS)………….49 2.4 In vivo microdialysis……………………………………………………..50 2.4.1 Microdialysis probe construction and calibration………………..50 2.4.2 In vivo microdialysis procedure………………………………….51 2.4.3 Pharmacological/Behavioral procedures – in vivo microdialysis..51 2.5 High performance liquid chromatography (HPLC)……………………...52 2.5.1 Analysis of dialysate samples……………………………………52 2.5.2 Analysis of tissue dopamine content……………………………..53 2.6 Drugs……………………………………………………………………..54 2.7 Data Analysis…………………………………………………………….55 vii 2.7.1 General considerations…………………………………………...55 2.7.2 Analyses for experiments in Chapter III…………………………55 2.7.3 Analyses for experiments in Chapter IV…………………………56 2.7.4 Analyses for experiments in Chapter V………………………….58 Chapter III Zolpidem Ameliorates Motor Impairments in the Unilaterally 6- hydroxydopamine-lesioned Rat 3.1 Rationale…………………………………………………………………61 3.2 Overview of Methods……………………………………………………62 3.3 Results…………………………………………………………………...64 3.3.1 Zolpidem induces a dose-dependent impairment on rotarod in intact rats…………………………………………………………64 3.3.2 Behavioral and neurochemical effects of unilateral 6-OHDA lesion……………………………………………………………..65 3.3.3 Zolpidem improves rotarod performance in unilaterally 6-OHDA- lesioned rats………………………………………………...……67 3.3.4 Zolpidem improves forelimb use symmetry in unilaterally 6- OHDA-lesioned rats……………………………………………...72 3.4 Summary of Results……………………………………………………...74 Chapter IV A Quantitative, Dopamine-correlated Measure of Levodopa-induced Behavioral Asymmetry in the Unilaterally 6-hydroxydopamine-lesioned Rodent 4.1 Rationale…………………………………………………………………76 4.2 Overview of Methods……………………………………………………78 4.2.1 Levodopa dose-response…………………………………………78 viii 4.2.2 Behavioral asymmetry scoring system (BASS)………………….78 4.2.3 In vivo microdialysis……………………………………………..79 4.3 Results……………………………………………………………………80 4.3.1 Behavioral effects of levodopa administration…………………..80 4.3.2 Levodopa-induced rotations and unilateral behavioral stereotypy are inversely correlated…………………………………………..83 4.3.3 Rotational behavior precedes stereotypy………………………...83 4.3.4 Rotational behavior poorly discriminates between doses………..86 4.3.5 Time spent displaying dyskinesia-like behavior is superior to rotational behavior in distinguishing between doses…………….89 4.3.6 BASS can be used to assess severity of LID-like behaviors as a function of dose……………………………………………….….93 4.3.7 BASS is superior to either rotational behavior and dyskinesia-like stereotypy alone………………………………………………….95 4.3.8 Levodopa-induced dopamine, 3,4-dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid efflux……………………………….97 4.3.9 Relationship between dopamine efflux and levodopa-induced behavioral asymmetry…………………………………………..100 4.3.10 BASS is highly correlated with dopamine efflux………………101 4.4 Summary of Results…………………………………………………….101 Chapter V Effects of Zolpidem on Levodopa-induced Behavioral Asymmetry in the Unilaterally 6-hydroxydopamine-lesioned Rat 5.1 Rationale………………………………………………………………..103 ix 5.2 Overview of Methods…………………………………………………..105 5.2.1 Behavioral effects of zolpidem on L-DOPA-induced behavioral asymmetry……………………………………….……………...105 5.2.2 Neurochemical effects of zolpidem on L-DOPA-induced DA efflux…………………………………………………….……...105 5.3 Results………………………………………………………………….107 5.3.1 Behavioral effects of levodopa/zolpidem administration………107 5.3.2 Effects of zolpidem on rotational behavior…………………….110 5.3.3 Zolpidem reduced dyskinesia-like stereotypy………………….112 5.3.4 Zolpidem reduced overall behavioral asymmetry……………...114 5.3.5 Zolpidem did not alter levodopa-induced striatal dopamine efflux……………………………………………………………117 5.3.6 Concomitant administration of zolpidem altered levodopa-induced rotations…………………………………………………………121 5.3.7 Concomitant administration of zolpidem did not alter dyskinesia- like stereotypy nor overall
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