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THE EFFECT of MGLUR7 ANTAGONIST TREATMENT on a DOPAMINE-INDUCED MURINE MODEL of OBSESSIVE-COMPULSIVE DISORDER a Dissertation

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THE EFFECT of MGLUR7 ANTAGONIST TREATMENT on a DOPAMINE-INDUCED MURINE MODEL of OBSESSIVE-COMPULSIVE DISORDER a Dissertation THE EFFECT OF MGLUR7 ANTAGONIST TREATMENT ON A DOPAMINE-INDUCED MURINE MODEL OF OBSESSIVE-COMPULSIVE DISORDER A Dissertation presented to the Faculty of the Graduate School at the University of Missouri-Columbia In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy by ASHLEY KRISTIN RAMSEY Dr. Todd Schachtman, Dissertation Supervisor JULY 2016 © Copyright by Ashley K. Ramsey, 2016 All Rights Reserved The undersigned, appointed by the dean of the Graduate School, have examined the dissertation entitled THE EFFECT OF MGLUR7 ANTAGONIST TREATMENT ON A DOPAMINE- INDUCED MURINE MODEL OF OBSESSIVE-COMPULSIVE DISORDER presented by Ashley K. Ramsey, a candidate for the degree of Doctor of Philosophy, and hereby certify that, in their opinion, it is worthy of acceptance. ___________________________________________ Professor Todd R. Schachtman ___________________________________________ Professor Matthew J. Will ___________________________________________ Professor Thomas M. Piasecki ___________________________________________ Professor Agnes Simonyi ACKNOWLEDGEMENTS The dissertation process (and perhaps more generally, the endeavor of scientific research) is practically impossible without the support of a community dedicated to the advancement of knowledge. The following dissertation was born from the combined efforts of many faculty, staff, students, and colleagues. I would specifically like to thank the following individuals/groups for their contributions to this dissertation, including their human-hours worked, encouragement, flexibility, inspiration, manuscript feedback, assistance with mouse colony care, assistance with maintaining a double-blind methodology, and overall guidance throughout the entire process: • My advisor, Dr. Todd Schachtman • My committee members, Drs. Agnes Simonyi, Matt Will, and Tom Piasecki • My research mentor and friend, Dr. Peter Serfozo • My students at IU-Southeast and Truman State University who served as trained behavioral analysis scorers • My fellow members of the Conditioning and Neuroscience lab at Mizzou • My fellow graduate students in psychology at Mizzou • Members of the Cognition and Neuroscience training area • The staff members of the Department of Psychology and the Graduate School at Mizzou ii TABLE OF CONTENTS Acknowledgements ............................................................................................................. ii List of Figures .................................................................................................................... iv List of Abbreviations ...........................................................................................................v Abstract .............................................................................................................................. vi Chapter 1. General Introduction .................................................................................................. 1 2. Experiment 1 ........................................................................................................... 12 Method ................................................................................................................. 13 Results .................................................................................................................. 17 Discussion ............................................................................................................ 18 3. Experiment 2 ........................................................................................................... 20 Method .................................................................................................................. 22 Results ................................................................................................................... 24 Discussion ............................................................................................................. 32 4. General Discussion .................................................................................................. 34 References ........................................................................................................................ 37 Vita .....................................................................................................................................55 iii LIST OF FIGURES Figure Page 1. Mean choices until alternation for Experiment 1 .........................................................17 2. Mean total alternations for Experiment 1 ....................................................................18 3. Mean choices until alternation for Experiment 2 across sensitization trials ................24 4. Main effects of quinpirole on grooming frequency, rearing frequency, number of visits to object 1, and time between visits to object 1 for sensitization data collapsed over MMPIP dose ...........................................................25 5. Effect of quinpirole and MMPIP on the percentage of total visits occurring at object 1 across all injection days .................................................................................26 6. Effect of quinpirole and MMPIP on the percentage of total visits occurring at object 4 across all injection days .................................................................................27 7. Effect of trial latency on grooming frequency across all treatment groups .................27 8. Effect of MMPIP on grooming frequency ...................................................................28 9. Effect of quinpirole and trial latency on number of visits to object 3 across the sensitization period ......................................................................................................29 10. Effect of quinpirole and MMPIP on rearing frequency ...............................................30 11. Effect of quinpirole and MMPIP on the percentage of total visits occurring at object 3 across all injection days .................................................................................30 12. Effect of MMPIP and trial latency on grooming frequency for injection day 17 collapsed over quinpirole dose .....................................................................................31 13. Effect of MMPIP and trial latency on time between visits to object 2 for injection day 17 collapsed over quinpirole dose ..........................................................31 iv LIST OF ABBREVIATIONS ACUC: Animal Care and Use Committee CBT: Cognitive Behavioral Therapy CNS: Central Nervous System CSTC: Corticostriatal-Thalamocortical DAT: Dopamine Transporter GPe: Globus Pallidus Externa GPi/SNr: Globus Pallidus Interna/Substantia Nigra Pars Reticula iGlu(R): Ionotropic Glutamate (Receptor) i.p.: Intraperitoneal mGlu(R): Metabotropic Glutamate (Receptor) NAC: N-Acetylcysteine OCD: Obsessive-Compulsive Disorder PFC: Prefrontal Cortex QNP: Quinpirole SRI: Serotonin Reuptake Inhibitor SSRI: Selective Serotonin Reuptake Inhibitor SUD: Substance Use Disorder vmPFC: Ventromedial Prefrontal Cortex v THE EFFECT OF MGLUR7 ANTAGONIST TREATMENT ON A DOPAMINE- INDUCED MURINE MODEL OF OBSESSIVE-COMPULSIVE DISORDER Ashley K. Ramsey Todd R. Schachtman, Dissertation Supervisor ABSTRACT Obsessive-compulsive disorder (OCD) is an incapacitating anxiety disorder characterized by unwanted, intrusive thoughts that lead to repetitive, ritualistic behaviors. Current treatments for OCD are only efficacious in a small portion of its sufferers. Animal models of OCD may lead to the development of novel treatment options such as those that modulate the glutamatergic system. The current study examined the effect of a metabotropic glutamate receptor 7 (mGluR7) antagonist, MMPIP, on two dopamine agonist-induced murine behavioral models of OCD. Although the T-maze alternation model of OCD failed to produce compulsive behaviors in the current study, the open field compulsive checking model of OCD did increase OCD-like behaviors, which were reversed after MMPIP administration. These results suggest that decreases in mGluR7 activity may provide a novel avenue of exploration for the treatment of OCD. vi THE EFFECT OF MGLUR7 ANTAGONIST TREATMENT ON A DOPAMINE- INDUCED MURINE MODEL OF OBSESSIVE-COMPULSIVE DISORDER Obsessive-compulsive disorder (OCD) is a debilitating, time- and effort- consuming clinical anxiety disorder characterized by unwanted, intrusive thoughts, impulses, or images (obsessions) that cause marked anxiety and/or by repetitive, ritualistic behaviors (compulsions) aimed at reducing the anxiety caused by the obsessions. OCD is a chronic disorder affecting the quality of life of 1-3% of the world population. Furthermore, financial setbacks from treatment and lost productivity are in excess of $8 billion annually (Rasmussen & Eisen, 2002). Common obsessions include thoughts/fears of contamination, aggressive thoughts, a need for symmetry, and somatically focused thoughts. Common compulsions include checking, repeating, washing, counting, ordering, and hoarding (van den Heuvel et al., 2008). Current neuroimaging evidence consistently points to faulty corticostriatal- thalamocortical (CSTC) circuitry and abnormal activation of the orbitofrontal cortex, striatum, thalamus, and anterior cingulate cortex of OCD patients (Grachev et al., 1998; Remijnse et al., 2006; Saxena et al., 1998; van den Heuvel, 2005; for review see El Mansari & Blier., 2006). Within this basal ganglia circuit, there is both a direct and an indirect pathway connecting
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