UNIQUE PHARMACODYNAMIC PROFILE OF METHYLPHENIDATE: SELF- ADMINISTRATION-INDUCED DOPAMINE SYSTEM ALTERATIONS BY ERIN SUE CALIPARI A Dissertation Submitted to the Graduate Faculty of WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES In Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Program in Neuroscience December 2013 Winston-Salem, North Carolina Approved by: Sara R. Jones, Ph.D., Advisor Thomas J. Martin, Ph.D., Chairman Rong Chen, Ph.D. Brian McCool, Ph.D. Steven Childers, Ph.D ii DEDICATION AND ACKNOWLEDGEMENTS First and foremost, I want to thank my advisor, Sara R. Jones, Ph. D. She gave me the freedom to explore many of my own interests while still providing important and insightful input to improve my projects and my writing. She gave her full support to my training at all times and helped me to develop as both a scientist and a person. I truly enjoyed working with her and admire her work ethic and dedication. The example that she has set for me will have a lasting impact beyond my scientific career. Second, I would like to thank the members of the Jones’ lab. I could not possibly thank them enough for all of the help and support that they have given me over the years. Mark J. Ferris, Ph. D, was instrumental in my training and often put as much effort into my projects as he did into his own. He was always there when I needed advice and although I was difficult to work with at times he always supported me. Jordan Yorgason was there with me every step of the way and helped me figure everything out, even when it was inconvenient for him. Jordan has the ability to fix anything that is broken, and I could not have done any of my work without his programming, soldering, or electronics skills. Mark and Jordan have become colleagues and friends (whether they like it or not) that I hope to continue to work with throughout my career. I would also like to thank Joanne Konstantopoulos and Jason Locke for their training and help with many of my projects. Without their willingness to cover for me, even on weekends, none of this work would have been possible. Also, I would like to thank the other members of the Jones lab, Anushree N. Karkhanis, Ph. D, Jamie Rose, James Melchior, and Cody Siciliano. Because of them, I enjoyed coming to work every day. The lab has been like my second iii family, first at times, and there is not anywhere else where I could have had a better graduate experience. I would also like to thank the members of my dissertation committee Drs. Martin, McCool, Chen, and Childers. They have been a source of advice and support throughout my graduate career and played a large role in the development of this dissertation. Additionally, their comments on my proposal contributed greatly to the National Research Service Award that I was awarded from the National Institute on Drug Abuse, and for that I am very grateful. Special thanks go to the Department of Physiology and Pharmacology and the Neuroscience program. The people within this department contributed greatly to this dissertation in many ways. The collaborative environment at Wake Forest University School of Medicine allowed me to learn numerous techniques and skills, many of which are included within this dissertation. I was able to form a network of collaborators that I will keep in touch with throughout my career. Additionally, the advice and support that I was given when applying for grants and postdoctoral positions was paramount to my success. I would also like to thank my family. My mother, Ellen, and my father, John, have given me their full support throughout my entire life, but especially throughout my graduate career. They were constant sources of encouragement that kept me going during difficult times. Also, I would like to thank my sister, Megan, and brother, Brad. They are two of the smartest people that I know and they have motivated me to work hard and dedicate myself completely to anything and everything that I do. iv And finally, I would like to thank the extracurricular groups and activities I was a part of in my spare time. The Phys/Pharm softball team allowed me to display my athletic prowess and make friends within the department. It was a consistent time each week for me to spend time with Alison Arter and Sarah Kromrey, and for that I am particularly grateful, although it is unlikely that anyone else is. v TABLE OF CONTENTS LIST OF TABLES AND FIGURES................................................................................ viii LIST OF ABBREVIATIONS .......................................................................................... xiv ABSTRACT ................................................................................................................... xviii PREFACE ........................................................................................................................ xxi Chapters CHAPTER I NEUROCHEMICAL AND BEHAVIORAL CONSEQUENCES OF METHYLPHENIDATE (MPH) SELF-ADMINISTRATION: MPH IS UNIQUE IN ITS ACTIONS AT THE DOPAMINE TRANSPORTER ........................................................ 1 Manuscript prepared for submission in Brain Research Reviews, 2013 CHAPTER II EXTENDED ACCESS COCAINE SELF-ADMINISTRATION RESULTS IN TOLERANCE TO THE DOPAMINE-ELEVATING AND LOCOMOTOR STIMULATING EFFECTS OF COCAINE ..................................................................... 59 Published in The Journal of Neurochemistry, in press, 2013 CHAPTER III WITHDRAWAL FROM EXTENDED-ACCESS COCAINE SELF- ADMINISTRATION RESULTS IN DYSREGULATED FUNCTIONAL ACTIVITY AND ALTERED LOCOMOTOR ACTIVITY IN RATS .............................................. 146 Published in European Journal of Neuroscience, in press, 2013 CHAPTER IV TEMPORAL PATTERN OF COCAINE INTAKE DETERMINES TOLERANCE VS SENSITIZATION OF COCAINE EFFECTS AT THE DOPAMINE TRANSPORTER ........................................................................................................................................ .117 Published in Neuropsychopharmacology, in press, 2013 CHAPTER V METHYLPHENIDATE AND COCAINE SELF-ADMINISTRATION PRODUCE DISTINCT DOPAMINE TERMINAL ALTERATIONS .............................................. 146 vi Published in Addiction Biology, in press, 2013 CHAPTER VI METHYLPHENIDATE AMPLIFIES THE POTENCY AND REINFORCING EFFECTS OF AMPHETAMINES BY INCREASING DOPAMINE TRASNPORTER EXPRESSION ................................................................................................................ 184 Published in Nature Communications, in press, 2013 CHAPTER VII UNIQUE PROFILE OF METHYLPHENIDATE-INDUCED DOPAMINE SYSTEM KINETICS: RELEASE PROFILE OF A BLOCKER AND UPTAKE PROFILE OF A RELEASER .................................................................................................................... 218 Manuscript prepared for submission in PLoS One CHAPTER VIII INTERMITTENT ACCESS METHYLPHENIDATE SELF-ADMINISTRATION RESULTS IN A SENSITIZED DOPAMINE SYSTEM................................................ 250 Manuscript prepared for submission in Neuroscience, 2013 CHAPTER IX DISCUSSION ................................................................................................................. 285 APPENDIX I CONSERVED DORSAL-VENTRAL GRADIENT OF DOPAMINE RELEASE AND UPTAKE RATE IN MICE, RATS, AND RHESUS MACAQUES .............................. 325 Published in Neurochemistry International, 61(7):986-9, 2012 APPENDIX II AMPHETAMINE MECHANISMS AND ACTIONS AT THE DOPAMINE TERMINAL REVISITED .............................................................................................. 347 Published in The Journal of Neuroscience, 33(21):8923-5, 2013 APPENDIX III AMERICAN CHEMICAL SOCIETY: COPYRIGHT CLEARANCE FORM ............. 355 vii APPENDIX IV NEUROPSYCHOPHARMACOLOGY: COPYRIGHT CLEARANCE FORM ........... 357 APPENDIX V ADDICTION BIOLOGY: COPYRIGHT CLEARANCE FORM ................................. 360 APPENDIX VI NEUROCHEMISTRY INTERNATIONAL: COPYRIGHT CLEARANCE FORM .... 368 CHAPTER X CURRICULUM VITA ................................................................................................... 374 viii LIST OF TABLES AND FIGURES TABLES Chapter III 1 Effect of 48 h withdrawal from a five-day binge cocaine self- administration on rates of local cerebral glucose utilization in rat brain……………………………………………………………...99 FIGURES Chapter I 1 Animals acquire methylphenidate (MPH) self-administration at a faster rate than cocaine (COC) self-administration……………...12 2 Methylphenidate (MPH) self-administration increases the preferred intake level and reinforcing efficacy of MPH……………………18 3 Increased dopamine transporter (DAT) levels increase the potency of psychostimulant releasers……………………………………..42 Chapter II 1 Cocaine self-administration results in escalation of first-hour cocaine intake…………………………………………………….67 2 Reduced dopamine (DA) release and uptake following cocaine self-administration……………………………………………….68 3 Cocaine self-administration results in tolerance to the dopamine transporter (DAT)-inhibiting and dopamine (DA)-elevating effects of cocaine………………………………………………………...71 4 Cocaine self-administration results in tolerance to the locomotor ix activating effects of acute cocaine administration……………….73 Chapter III 1 Cocaine self-administration results in escalation of rate of cocaine intake……………………………………………………………..93 2 Cocaine self-administration results in reduced locomotor response to a novel environment…………………………………………...94 3 Cocaine self-administration does not alter baseline locomotion...95 4