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The Relationship of Alcohol Dependence to Monoamine Oxidase A

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The Relationship of Alcohol Dependence to Monoamine Oxidase A The Relationship of Alcohol Dependence to Monoamine Oxidase A by Brittany Matthews 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 Brittany Matthews 2015 The Relationship of Alcohol Dependence to Monoamine Oxidase A Brittany Matthews Doctor of Philosophy Department of Pharmacology and Toxicology University of Toronto 2015 Abstract Background: Alcohol dependence (AD) is a substance abuse disorder characterized by compulsive alcohol seeking and intake, combined with a negative emotional state during withdrawal. AD is also associated with markers of apoptosis and/or oxidative stress across multiple organs. Monoamine oxidase A (MAO-A) is an important enzyme that participates in the cellular response to oxidative stress, and is elevated during major depressive episodes, somewhat more robustly in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC). It is unknown whether MAO-A levels are abnormal in AD. The current studies examine whether: i) MAO-A level is elevated in the PFC and ACC in AD in humans. ii) Chronic harman exposure, a MAO-A inhibitor found in alcoholic beverages, upregulates MAO-A in the PFC and ACC of rodents. iii) Chronic alcohol exposure upregulates MAO-A in the PFC and ACC of rodents. Methods: i) Sixteen participants with AD underwent [ 11 C]-harmine positron emission tomography to determine MAO-A distribution volume (VT), an index of MAO-A level. ii ii) Rats were treated with harman for 21 days (0, 2, 5, 15 mg/kg/day) via osmotic minipump. MAO-A protein and activity levels, measured with Western blot and a spectrophotometric assay respectively, were assessed immediately and after 8-hour withdrawal. iii) Rats were exposed to alcohol vapor for 8 weeks, 17 hours per day. MAO-A protein/activity levels were assessed immediately and after 24-hour, 4-day, and 21-day withdrawal. Results: i) MAO-A V T was significantly greater in all brain regions analyzed in AD. ii) MAO-A protein/activity levels were not altered by harman administration. iii) MAO-A protein/activity levels were elevated in the PFC and ACC after 24-hour withdrawal from alcohol exposure. There were no changes at any other timepoints. Conclusion: These findings identify elevated MAO-A level as a new pathological marker present in AD that is therapeutically targetable through direct inhibition. MAO-A protein/activity levels were not changed by harman administration, suggesting chronic MAO-A inhibition does not alter MAO-A level. The human PET findings, measured in early withdrawal from alcohol dependence, were replicated in the rodent model of chronic alcohol exposure in the PFC and ACC, suggesting that alcohol exposure likely led to elevated MAO-A in AD. iii Acknowledgments First, I would like to thank my supervisor Dr. Jeffrey Meyer and co-supervisor Dr. Stephen Kish for giving me the opportunity to work under their supervision at the Centre for Addiction and Mental Health. They have been excellent mentors and I am grateful for their guidance and encouragement throughout my doctoral program. I would also like to thank my PhD supervisory committee members, Drs. Jose Nobrega, Isabelle Boileau, and Junchao Tong for their valuable insight and helpful suggestions. A special thank you to the members of both the Meyer and Kish lab, as well as the PET imaging technicians, who have shared their technical expertise and contributed to various parts of my PhD thesis. Finally, I would like to thank my family and friends for their unconditional love and support, without which the completion of this thesis would not have been possible. iv Table of Contents List of Tables .............................................................................................................................. viii List of Figures ............................................................................................................................... ix List of Abbreviations ................................................................................................................... xi 1 Introduction .............................................................................................................................. 1 1.1 Overview ............................................................................................................................ 1 1.1.1 Statement of the Problem ........................................................................................ 1 1.1.2 Purpose of the Study ............................................................................................... 2 1.2 Background ....................................................................................................................... 3 1.2.1 Importance of Alcohol Dependence ....................................................................... 3 1.2.2 Brief Review of Major Structural and Neurochemical Abnormalities in Alcohol Dependence ............................................................................................... 5 1.2.2.1 Structural Alterations ................................................................................ 5 1.2.2.2 Cellular Alterations .................................................................................. 6 1.2.2.3 Markers associated with Apoptosis in Alcohol Dependence ................... 8 1.2.2.4 Markers associated with Oxidative Stress in Alcohol Dependence ......... 9 1.2.2.5 Monoamine Receptor and Transporter Abnormalities ........................... 11 1.2.3 Alcohol Dependence and Mood ............................................................................ 14 1.2.4 Pathways and Common Pathologies of Comorbid Alcohol Dependence and Major Depressive Disorder ................................................................................... 18 1.2.5 Monoamine Oxidase A ......................................................................................... 20 1.2.5.1 General Properties of MAO-A ............................................................... 20 1.2.5.2 Substrates of MAO-A ............................................................................. 26 1.2.5.3 Radiotracers for Imaging MAO-A ......................................................... 28 1.2.6 Role of MAO-A in Mood Disorders ..................................................................... 31 1.2.7 Monoamine Oxidase A in Alcohol Dependence in Humans ................................ 33 1.2.8 Rationale for Investigating MAO-A in Alcohol Dependence .............................. 38 v 1.2.8.1 Alcohol Dependence and Dysphoric Mood ........................................... 38 1.2.8.2 Monoamine Oxidase A and Models of Alcohol Dependence in Rodents ................................................................................................... 38 1.2.8.3 Alcohol Dependence and Predisposition to Apoptosis .......................... 39 1.2.9 Role of Monoamine Oxidase A Inhibitor Harman in Addiction .......................... 41 1.3 Study Objectives and Research Hypotheses ................................................................. 47 2 Methods ................................................................................................................................... 51 2.1 Human PET Imaging Study of MAO-A in Alcohol Dependence ............................... 51 2.1.1 Study Participants and Protocol for PET Imaging Scan ....................................... 51 2.1.2 PET Image Acquisition and Analysis ................................................................... 53 2.1.3 Statistical Analysis ................................................................................................ 56 2.2 Studies of the effect of Harman and Alcohol Exposure on MAO-A in Rodents ....... 57 2.2.1 Animals ................................................................................................................. 57 2.2.2 Harman Osmotic Minipump Exposure ................................................................. 57 2.2.3 Ethanol Vapor Exposure ....................................................................................... 58 2.2.4 Measurement of MAO Protein .............................................................................. 60 2.2.5 Measurement of MAO Activity ............................................................................ 61 2.2.6 Measurement of GFAP ......................................................................................... 62 2.2.7 Statistical Analysis ................................................................................................ 63 3 Results ..................................................................................................................................... 64 3.1 Human PET Imaging Study of MAO-A in Alcohol Dependence ............................... 64 3.1.1 Difference in MAO-A V T between the Alcohol Dependent Group and Healthy Controls ................................................................................................................. 64 3.1.2 Relationship between MAO-A V T and Duration of Heavy Alcohol Use ............. 67 3.1.3 Relationship between MAO-A V T and Other Clinical Features ........................... 69 3.1.4 Additional Characteristics of the Alcohol Dependent Group ............................... 73 3.2 Studies of the effect of Harman and Alcohol Exposure on MAO-A in Rodents ....... 74 vi 3.2.1 Effect of Harman Exposure on MAO ..................................................................
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