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Nicotinamide Co-Administration With NICOTINAMIDE CO-ADMINISTRATION WITH METHAMPHETAMINE: EFFECTS ON THE P450 AND DOPAMINERGIC SYSTEMS By JOHN DERICK PAULSON Bachelor of Science Oklahoma State University Stillwater, Oklahoma 1994 Master of Science Oklahoma State University Stillwater, Oklahoma 1995 Submitted to the Faculty of the Graduate College of the Oklahoma State University in partial fulfillment of the requirements for the Degree of DOCTOR OF PHILOSOPHY December, 2005 NICOTINAMIDE CO-ADMINISTRATION WITH METHAMPHETAMINE: EFFECTS ON THE P450 AND DOPAMINERGIC SYSTEMS Dissertation Approved: David Wallace, Ph.D. Dissertation Adviser Cyril Clarke, Ph.D. Charles Sanny, Ph.D. Craig Stevens, Ph.D. A. Gordon Emslie Dean of the Graduate College ii ACKNOWLEDGMENTS After seven years of graduate education at Oklahoma State University Center for Health Sciences I have come to know the faculty and staff as family. It would take to much time to list all those who have touched my life in one way or another while working towards my degree at this institution. Therefore, I would just like to say thank you to each and every member who I have had the opportunity to get to know over the past seven years. It has been my pleasure to know and work with you. I would also like to acknowledge my friends and colleagues at the Tulsa Police Department. I wish to express my sincere appreciation and gratitude to my major advisor and friend, Dr. David Wallace. I can never repay his selfless donation of time, money, and support. I have been around to celebrate the birth of his daughter, Madison Brooke Wallace, and to morn the loss of his mother, father, and doctoral mentor, Dr. Ralph Dawson Jr. Dr. Wallace, I wish you the best of luck with your family and career. I would also like to thank Dr. Cyril Clarke, Dr. Charles Sanny, and Dr. Craig Stevens for serving on my committee. I appreciate each of you and thank you for your input and guidance. Additionally, I thank you for always being there and motivating me to continue my research no matter how rough the road was at the time. Two other people that have been extremely important to my success are Dr. Gary Ostrander and Dr. Jerry O’Donnell. These two individuals have molded me into the scientist and man I am today. I thank them from the bottom of my heart for being there iii for me and pushing me to achieve things I would have never thought possible. You two will never know how much you have shaped my life into what it is today. Thank you! I cannot conclude without expressing my thanks to Dr. Doris Patneau for providing the numerous rats needed for my experiments. Also, I appreciate all of the late night and very early morning pep talks by Dr. Dorothy Turetski. I could not have pulled all those all-nighters without you. Mr. David Money has become a good friend of mine over the years and I thank him for his support and assistance with my literature search and all of his kind words. I also am grateful for the rest of the library staff and for all of the assistance over the years. In conclusion, I am forever grateful for the love and support that my friends and family have given me over the years. My parents, Neal and Carol Paulson, and aunt, Mary Nell Thompson, have always been there for me. Finally, this dissertation is dedicated to my grandmother, Dorothy Nell Jetton, for all of the love and support she has provided me over the years. I will never forget everything you have done for me. iv TABLE OF CONTENTS Chapter Page I. INTRODUCTION AND LITERATURE SEARCH 1.1 Introduction........................................................................................................1 1.2 History of methamphetamine.............................................................................1 1.2.1 Illicit production of amphetamine and methamphetamine .....................10 1.3 Physical properties of methamphetamine ........................................................18 1.4 Administration .................................................................................................21 1.5 Clinical effects .................................................................................................22 1.6 Pattern of abuse................................................................................................26 1.7 Neurochemistry of addiction............................................................................29 1.7.1 Dopamine hypothesis..............................................................................29 1.7.2 Dopamine synthesis ................................................................................31 1.7.3 Dopamine release....................................................................................32 1.7.4 Central dopaminergic systems ................................................................34 1.7.5 Dopamine and addiction .........................................................................34 1.7.6 Common properties of the dopaminergic receptor subtypes ..................37 1.7.6.1 Dopamine receptor gene .................................................................37 1.7.6.2 Dopamine receptor expression........................................................38 1.7.6.3 D1-like receptor subfamily..............................................................38 1.7.6.4 D2-like receptor subfamily..............................................................39 1.7.7 Dopamine metabolism ............................................................................43 1.7.8 Dopamine transport protein ....................................................................43 1.7.9 Effects of methamphetamine on dopaminergic system ..........................44 1.7.9.1 Exchange diffuse model..................................................................45 1.7.9.2 Weak base model ............................................................................45 1.7.10 Other neurotransmitters ........................................................................48 1.8 Animal model...................................................................................................48 1.9 Methamphetamine dosage ...............................................................................49 1.10 Enzyme metabolism.......................................................................................51 1.10.1 Methamphetamine metabolism.............................................................51 1.10.2 Enzyme drug metabolism .....................................................................54 1.10.3 Cytochrome P450 system .....................................................................54 1.10.4 Drug interactions...................................................................................55 1.10.5 Enzyme inhibitors .................................................................................56 1.10.6 Enzyme induction .................................................................................57 1.11 Cytochrome P450...........................................................................................57 1.11.1 Cytochrome P450 nomenclature...........................................................57 v 1.11.2 CYP1A subfamily.................................................................................57 1.11.3 CYP2D subfamily.................................................................................58 1.11.4 CYP2C subfamily.................................................................................59 1.11.5 CYP3A subfamily.................................................................................60 1.12 Metabolism studies ........................................................................................62 1.12.1 Methods for studying metabolism in vitro and in vivo .........................62 1.12.2 cDNA expressed enzymes ....................................................................63 1.12.3 Liver microsomes..................................................................................63 1.12.4 Human hepatocytes...............................................................................64 1.13 High throughput inhibition assays .................................................................65 1.13.1 Selection of appropriate probes and inhibitors .....................................65 1.13.1.1 CYP2D6/CYP2D2 fluorescent probes.........................................65 1.13.1.2 CYP2D6/CYP2D2 selective inhibitor .........................................66 1.13.1.3 CYP3A4 fluorescent probe..........................................................66 1.13.1.4 CYP3A4 selective inhibitor .........................................................66 1.14 Animal studies ...............................................................................................66 1.15 Human abuse pattern......................................................................................67 1.16 Vitamin B-3 ...................................................................................................69 1.17 Significance....................................................................................................72 II. PRELIMINARY STUDIES 2.1 Dose ratio determination..................................................................................74 2.1.1 Introduction.............................................................................................74 2.1.2 Chemicals................................................................................................74 2.1.3 Methods...................................................................................................74
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