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Identification of Pharmacological and Molecular Mechanisms Involved in Nicotine Withdrawal Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2008 Identification of Pharmacological and Molecular Mechanisms involved in Nicotine Withdrawal Kia Jackson Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Medical Pharmacology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/1616 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. School of Medicine Virginia Commonwealth University This is to certify that the dissertation prepared by Kia Janelle Jackson entitled IDENTIFICATION OF PHARMACOLOGICAL AND MOLECULAR MECHANISMS INVOLVED IN NICOTINE WITHDRAWAL has been approved by his or her committee as satisfactory completion of the thesis or dissertation requirement for the degree of Doctor of Philosophy. Dr. M. Imad Damaj, School of Medicine _______________________________________________________________________ Dr. Aaron Lichtman, School of Medicine Dr. Michael Miles, School of Medicine Dr. Joseph Porter, College of Humanities and Sciences Dr. Robert Tombes, College of Humanities and Sciences Dr. William Dewey, Departmental Chair, Pharmacology and Toxicology i Dr. Jerome F. Strauss, III, Dean of the School of Medicine Dr. F. Douglas Boudinot, Dean of the School of Graduate Studies [Click here and type the Month, Day and Year this page was signed.] © Kia Janelle Jackson, 2008 All Rights Reserved INDENTIFICATION OF PHARMACOLOGICAL AND MOLECULAR MECHANISMS INVOLVED IN NICOTINE WITHDRAWAL A Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University by KIA JANELLE JACKSON Bachelor of Science North Carolina A&T State University May 2004 Director: DR. M. IMAD DAMAJ ASSOCIATE PROFESSOR, DEPARTMENT OF PHARMACOLOGY AND TOXICOLOGY Virginia Commonwealth University Richmond, Virginia December, 2008 Acknowledgements “I have learned that success is to be measured not so much by the position that one has reached in life as by the obstacles which he has overcome while trying to succeed.”- Booker T. Washington I’d like to take this opportunity to thank those who helped me overcome those obstacles. A million thanks to my advisor, Dr. M. Imad Damaj, for his patience, guidance and encouragement. I was told from the beginning that the most important decision I would make as a graduate student was choosing an advisor. As I reach the end of this long road, I genuinely believe that I couldn’t have made a better decision. Thanks to the members of my graduate committee: Dr. Michael Miles, for his thought-provoking questions that helped build my critical thinking, and for his expertise in the use of transgenic animals; Dr. Joseph Porter, for his suggestions and behavioral expertise; Dr. Robert Tombes, for taking time to meet and discuss with me any questions or concerns I had about CaMKII assays; and Dr. Aron Lichtman, who I cannot thank enough for providing his time to my committee and for his statistical expertise. I’d especially like to thank Dr. Billy Martin, whose wisdom and advice helped me in writing this dissertation. If anyone just so happens to ask me about receptor theory, I have him to thank for the ability to answer those questions! I would also like to thank Dr. Jenny Wiley for planting the seed of interest in Pharmacology as my high school mentor in the Minority Summer Research Program in 1999, Dr. Darlene Brunzell for her helpful paper writing tips, and Dr. William Dewey for his recommendations and grant writing tips. I’d like to express my sincere thanks to all the members, past and present, of the Damaj lab; Tie Han, Lisa Merritt, Carrie Walters, Sarah Sanjakdar, Pretal Patel, Shakir Alsharari, Dena Kota, Cindy Evans, Ali Saaed, and Hadi Anwar. Each of you in some way contributed to my growth as a scientist and helped keep me sane! I will never forget how wonderful you all are. Last, but not least, I’d like to thank my family and friends for their unending support and encouragement. My parents, Lynda and Alvin Kelley, who listened to my presentations and frustrations, gave me teaching advice, and supported me in more ways than I can name; my father, Dr. Cephus Jackson, for giving me guidance on the road to obtaining my doctoral degree; grandparents, Bill and Glenna Loving for always believing in me, and a score of others who have always been in my corner in so many ways. Words cannot express how grateful and blessed I feel having such wonderful and supportive people in my life. I’m glad I make you proud. Table of Contents Page Acknowledgements ............................................................................................................. v List of Tables....................................................................................................................... x List of Figures .................................................................................................................... xi List of Abbreviations......................................................................................................... xv Abstract ............................................................................................................................ xvi Chapter 1 GENERAL INTRODUCTION ......................................................................... 1 A.Tobacco and Nicotine Dependence .......................................................... 1 B. Molecular and Pharmacological Mechanisms of Nicotine Withdrawal ................................................................................................... 3 C. Calcium Dependent Mechanisms of Nicotine Dependence and Withdrawal ................................................................................................ 10 D. Behavioral Models of Nicotine Withdrawal .......................................... 15 E. Transgenic Animals: A Complementary Approach to Pharmacological Methods ...................................................................................................... 18 F. Dissertation Objectives........................................................................... 21 2 CHARACTERIZATION OF A NICOTINE CONDITIONED PLACE AVERSION MOUSE MODEL ......................................................... 25 A. Introduction............................................................................................ 25 B. Methods.................................................................................................. 27 C. Results .................................................................................................... 31 D. Discussion .............................................................................................. 40 3 THE ROLE OF α4α6β2* NICOTINIC RECEPTORS IN NICOTINE WITHDRAWAL ............................................................................................. 45 A. Introduction............................................................................................ 45 B. Methods.................................................................................................. 47 C. Results .................................................................................................... 52 D. Discussion .............................................................................................. 68 4 IDENTIFICATION OF ADDITIONAL NICOTINIC RECEPTOR SUBUNITS INVOLVED IN NICOTINE WITHDRAWAL ......................... 74 A. Introduction............................................................................................ 74 B. Methods.................................................................................................. 76 C. Results .................................................................................................... 79 D. Discussion .............................................................................................. 91 5 THE ROLE OF CALCIUM-DEPENDENT MECHANISMS IN NICOTINE WITHDRAWAL .................................................................... 96 A. Introduction............................................................................................ 96 B. Methods.................................................................................................. 98 C. Results .................................................................................................. 103 D. Discussion ............................................................................................ 123 6 IN VITRO CHARATERIZATION OF MOLECULAR MECHANISMS OF NICOTINE WITHDRAWAL: A ROLE FOR CAMKII AND SYNAPSIN I ................................................................................................. 129 A. Introduction.......................................................................................... 129 B. Methods................................................................................................ 133 C. Results .................................................................................................. 137 D. Discussion ............................................................................................ 160 7 GENERAL DISCUSSION A. Rationale and Summary of Overall Hypothesis .................................. 165 B. Nicotinic Receptor Subtypes have Differential Roles
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