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Copyright by Amanda Price 2018 The Dissertation Committee for Amanda Price certifies that this is the approved version of the following dissertation: Strategies to Identify Therapeutic Opportunities in the Treatment of Addictive Disorders Committee: Kathryn A. Cunningham, Ph.D., Mentor John A. Allen, Ph.D. Noelle C. Anastasio, Ph.D. Jonathan D. Hommel, Ph.D. F. Gerard Moeller, M.D. _______________________________ Dean, Graduate School Strategies to Identify Therapeutic Opportunities in the Treatment of Addictive Disorders by Amanda Elizabeth Price, B.S., B.S. Dissertation Presented to the Faculty of the Graduate School of The University of Texas Medical Branch in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas Medical Branch June 2018 Dedication For my parents, who instilled in me a love for knowledge. For my husband, who has supported me throughout. And for my children, who inspire me every day. Acknowledgements I would like to thank my mentor, Dr. Kathryn Cunningham, for her continued support, flexibility, and the many opportunities she provided me throughout the years. I would like to thank my F30 co-mentor, Dr. Noelle Anastasio, for always challenging me to become a better scientist and for her willingness to always help in any way she could. I would also like to thank Dr. John Allen, Dr. Jonathan Hommel, and Dr. F. Gerard Moeller, for serving on my dissertation committee and asking insightful questions that strengthened this work. I would like to thank Ms. Sonja Stutz for her intimate involvement in my projects, the time she spent teaching me technical skills, and her help designing and interpreting experiments. I would also like to thank Mr. Robert Fox for his assistance with animal studies and planning experiments. I am especially grateful for the former and current graduate students, post-docs, and other researchers who have provided so much assistance through the years, especially Dr. Claudia Soto, Mr. Dennis Sholler, Ms. Christina Merritt, and Ms. Victoria Brehm, Dr. James Kasper, Dr. Daniel Felsing, Dr. Erik Garcia, Dr. Erica Holliday, and Dr. Harshini Neelakantan. I would also like to thank the people of the Center for Addiction Research (Ms. Maria Garcia, Ms. Kirsty Foss, Ms. Rosa Alvidrez, and Dr. Marcy Jordan), the Neuroscience Graduate Program (Dr. Owen Hamill and Ms. Aurora Galvan), and the M.D.-Ph.D. combined degree program (Dr. Lawrence Sowers, Dr. Jose Barral, and Ms. Claiborne Fant) who have given me great administrative support throughout the years. Finally, I would like to thank my family, especially my parents Roxanne and Horace Price, Jr., for teaching me the value of education and shaping me into the woman I am today, and my husband Benjamin Porche, who always gave valuable input as an outsider to science and had the perfect Excel formula for whatever I needed. This work was supported by NIH grants DA007287, DA042617, DA033935, DA020087, DA038999, the Klarman Family Foundation, and the Center for Addiction Research. iv Strategies to Identify Therapeutic Opportunities in the Treatment of Addictive Disorders Publication No._____________ Amanda Elizabeth Price, Ph.D. The University of Texas Medical Branch, 2018 Supervisor: Kathryn A. Cunningham Addictive disorders are a collection of maladaptive behaviors characterized by the uncontrolled use of a rewarding substance. These include substance use disorders, binge eating disorder, certain subtypes of obesity, gambling disorder, and internet gaming disorder. Each of these disorders share similar behavioral characteristics that may be motivated by common neural substrates and molecular mechanisms. This dissertation aims to elucidate some of the drivers of addictive behaviors and proposes four strategies to identify therapeutic opportunities in the treatment of addictive disorders, with a special emphasis on binge eating disorder. The current work demonstrates an association between high fat food binge intake and cue reactivity, both of which are modulated by insula activity. Further, the clinically-approved serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist/inverse agonist pimavanserin and 5-HT2CR agonist lorcaserin used alone or in combination demonstrate efficacy in suppressing measures of binge eating. Pharmacological studies further show that activation of the 5-HT2CR may suppress binge eating by decreasing the reinforcing and motivational properties of high fat food. Finally, a possible role for a 5-HT2AR:5-HT2CR protein interaction in the protection against addictive behaviors is proposed. This dissertation concludes by discussing possible routes of implementation of the present findings into clinical practice. The strategies discussed – v neuronal modulation, behavioral-guided therapy, drug repurposing, and combined therapeutic approaches – offer great possibilities in the development of new therapeutic approaches in the treatment of addictive disorders. vi TABLE OF CONTENTS List of Tables xi List of Figures xii List of Abbreviations xiv Chapter 1: Introduction 1 Introduction ................................................................................................... 1 Mapping Diagnostic Criteria of SUD onto Other Addictive Disorders ............ 1 Strategies to Identify Therapeutic Opportunities in the Treatment of Addictive Disorders ............................................................................................. 2 Neuronal Modulation ............................................................................ 5 Behavior-Guided Therapy .................................................................... 6 Drug Repurposing ................................................................................ 8 Combined Therapeutic Approaches ..................................................... 10 Conclusions .................................................................................................. 11 Chapter 2: Anterior Insula Activity Regulates the Associated Behaviors of High Fat Food Binge Intake and Cue Reactivity 12 Introduction ................................................................................................... 12 Methods ........................................................................................................ 13 Animals ................................................................................................ 13 Food. .................................................................................................... 13 Operant Conditioning for HFF Self-Administration ................................ 13 Association Between HFF Binge Intake and Cue Reactivity ................. 14 Viral-Mediated Gene Transfer .............................................................. 15 Validation of Cellular Activation by CNO .............................................. 15 Insulaant Activation Effect on SF and HFF Intake .................................. 17 Insulaant Activation Effect on HFF Self-Administration and Cue Reactivity .................................................................................................... 19 Statistical Analyses .............................................................................. 21 Results ......................................................................................................... 21 Association Between HFF Binge Intake and Cue Reactivity ................. 21 Localization of hM3D within the Insulaant .............................................. 22 Validation of Cellular Activation by CNO .............................................. 23 Insulaant Activation Effect on SF and HFF Intake .................................. 24 vii Insulaant Activation Effect on HFF Cue Reactivity ................................. 26 Insulaant Activation Effect on FR Responding for HFF........................... 26 Insulaant Activation Effect on PR Responding for HFF .......................... 27 Discussion .................................................................................................... 28 Chapter 3: 5-HT2CR Activation Suppresses Binge Intake and the Reinforcing and Motivational Properties of High Fat Food 31 Introduction ................................................................................................... 31 Methods ........................................................................................................ 32 Animals ................................................................................................ 32 Food. .................................................................................................... 32 Drugs ................................................................................................... 33 WAY163909 Effect on HFF Binge Intake ............................................. 33 WAY163909 Effect on SF Non-Binge Intake ........................................ 34 Operant Conditioning for HFF Self-Administration ................................ 34 WAY163909 Effect on FR Responding for HFF.................................... 34 WAY163909 Effect on PR Responding for HFF ................................... 35 Statistical Analyses .............................................................................. 35 Results ......................................................................................................... 36 WAY163909 Effect on HFF Binge Intake ............................................. 36 WAY163909 Effect on SF Non-Binge Intake ........................................ 36 WAY163909 Effect on