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The Effect of Altering Brain CYP2B Activity on Nicotine Self-Administration Behaviour and Nicotine Levels in the Brain

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The Effect of Altering Brain CYP2B Activity on Nicotine Self-Administration Behaviour and Nicotine Levels in the Brain The Effect of Altering Brain CYP2B Activity on Nicotine Self-Administration Behaviour and Nicotine Levels in the Brain by Kristine Garcia A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Pharmacology and Toxicology University of Toronto © Copyright by Kristine Garcia 2016 The Effect of Altering Brain CYP2B Activity on Nicotine Self- Administration and Nicotine Levels in the Brain Kristine Garcia Doctor of Philosophy Pharmacology and Toxicology University of Toronto 2016 Abstract Cytochrome P450 (CYP) enzymes play an important role in drug metabolism. While CYPs are abundantly expressed in the liver, where CYP-mediated drug metabolism typically occurs, these enzymes are also expressed in other tissues such as the brain. Local brain drug metabolism can influence the response to drugs that act within the brain. The CYP subfamily 2B (CYP2B) is expressed in the brain and is responsible for metabolizing many central nervous system (CNS)- acting drugs including nicotine, the main psychoactive ingredient in cigarettes. Genetic variation in human CYP2B6 is associated with greater conversion to nicotine dependence and risk of relapse in smokers without influencing peripheral nicotine metabolism. This suggests that local brain nicotine metabolism could influence nicotine levels that in turn mediate nicotine reinforcement and resulting behaviours. The role of brain CYP2B activity in nicotine reinforcement was investigated by injecting a pharmacological CYP2B inhibitor into the brain of rats that then underwent nicotine self-administration (NSA), which models smoking behaviour. Inhibitor-treatment increased NSA acquisition, motivation to obtain nicotine and the number of sessions required to extinguish behaviour, suggesting that inhibiting brain CYP2B activity can augment nicotine-reinforced behaviour. The effect of brain CYP2B inhibition on brain nicotine levels following a nicotine injection was then investigated using in vivo microdialysis. Inhibitor ii treatment increased peak brain nicotine levels and nicotine levels within 0-45 minutes post- injection compared to vehicle, suggesting that inhibiting brain CYP2B activity reduced nicotine metabolism, resulting in higher brain nicotine levels. Inducing brain CYP2B, by a paradigm that increases CYP2B protein in the brain but not the liver, reduced brain nicotine levels within 15-45 minutes post-injection, suggesting that induction increased brain CYP2B activity and nicotine metabolism. These findings demonstrate that altering brain CYP2B activity can influence brain nicotine levels and that inhibiting brain CYP2B, which increases nicotine levels, may increase nicotine’s reinforcing effect consistent with the behaviours in NSA. This is also consistent with the behavioural differences associated with genetic variation in CYP2B6, suggesting that altered brain CYP2B activity may influence smoking behaviour. Thus, these findings provide evidence that brain CYPs can influence the local metabolism of its substrates and their resulting drug response. iii Acknowledgments I want to thank my supervisor, Dr. Rachel Tyndale, for all of her support throughout my graduate program. You allowed me to contribute my ideas for the work early on and gave me great feedback and mentorship towards completing these exciting projects. Thank you for being supportive of every direction we went with the work and supportive of improving my skills as a graduate student, researcher, and presenter. I also want to thank Dr. Anh Dzung Lê for his support throughout these years. You have also been very supportive of my ideas for experimental design and have been so helpful in discussing the interpretations and implications of the work. I thoroughly enjoyed working in your lab with you and your research staff. I want to thank the research staff from both the Tyndale and Lê labs, especially Fariba Baghai Wadji, Kathy Coen, Zhaoxia Li, Sharon Miksys, Bin Zhao, Maria Novalen for all of their help and support. Without them I wouldn’t have been able to carry out this work. I would also like to thank the graduate students that were along the ride with me: Catherine Wassenaar, Meghan Larin, Kaidi Zhou, and Charmaine Ferguson. You guys made the days of data analysis and paper writing fun times. Finally, I’d like to thank my family: my mom, dad, brother, and sister. You guys supported me through all of my graduate training and I want to thank you for being there for me. Thanks for listening to me talk about my work even though you didn’t understand everything and for accommodating me when experiment days were long. I definitely wouldn’t have been able to go back to school and do what I love without your support. Thanks so much. iv Table of Contents Abstract ........................................................................................................................................... ii Acknowledgments .......................................................................................................................... iv List of Tables ................................................................................................................................. ix List of Figures ................................................................................................................................. x List of Abbreviations ..................................................................................................................... xi Section 1. Introduction ................................................................................................................. 1 Statement of Problem ...................................................................................................................... 1 Purpose of the Study and Objective ................................................................................................ 2 Statement of Research Hypotheses and Rationale for Hypotheses ................................................ 3 Review of the literature ................................................................................................................ 5 1. Cytochrome P450 enzymes ....................................................................................................... 5 1.1. CYPs in the brain ..................................................................................................................... 6 1.1.1. CNS-acting drug substrates ................................................................................................... 6 1.1.2. Expression in the brain .......................................................................................................... 7 1.1.3. CYP activity in the brain ....................................................................................................... 9 1.1.4. The role of the CYP2 subfamily in the brain ........................................................................ 9 1.2. CYP2B ................................................................................................................................... 12 1.2.1. Isoforms expressed in the brain .......................................................................................... 12 1.2.2. CYP2B substrates ............................................................................................................... 13 1.2.3. Sources of CYP2B variation ............................................................................................... 16 1.2.3.4. Genetic variation in CYP2B6 ........................................................................................... 16 1.2.3.5. Non-genetic variation in CYP2B expression ................................................................... 18 1.2.3.5.1. CYP2B inducers ............................................................................................................ 19 1.2.3.5.2. CYP2B inhibitors .......................................................................................................... 20 1.2.4. Functional impact of variation in CYP2B activity ............................................................. 21 1.2.5. Functional impact of CYP2B variation in the brain ........................................................... 22 1.2.6. Rat model of CYP2B variation in the brain ........................................................................ 23 1.2.6.1. Brain CYP2B inhibition using MBIs ............................................................................... 23 1.2.6.2. Brain CYP2B induction using nicotine ............................................................................ 25 1.2.6.3. Drug response in rat model of brain CYP2B variation .................................................... 26 1.2.7. Role of brain CYP2B in smoking behaviour ...................................................................... 28 2. Nicotine and Smoking ............................................................................................................. 29 2.1. Nicotine in cigarettes ............................................................................................................. 29 2.2. Pharmacological action in the brain ....................................................................................... 30 2.2.1. Nicotinic acetylcholine receptors ........................................................................................ 30 2.2.2. Brain reward system ..........................................................................................................
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