PRECLINICAL MODELING of HABITUAL NICOTINE SEEKING by Andrew Loughlin a Thesis Submitted in Conformity with the Requirements
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PRECLINICAL MODELING OF HABITUAL NICOTINE SEEKING by Andrew Loughlin A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Pharmacology University of Toronto © Copyright by Andrew Loughlin (2015) Preclinical Modeling of Habitual Nicotine Seeking Andrew Loughlin Master of Science Graduate Department of Pharmacology University of Toronto 2015 Abstract Current theories of substance dependence suggest that contributions to compulsive drug use may include the aberrant recruitment of cognitive processes normally responsible for automatizing repeated behaviors, or “forming habits”. While evidence has shown that both ethanol and cocaine can abnormally accelerate the formation of drug-seeking habits, whether this could be the case for nicotine has received little attention. In the current work, subjects acquired self-administration of both intravenous nicotine and orally consumed saccharin in two separate daily operant sessions, receiving 10 sessions of FR1 training for each reinforcer. Behavioral assays of “aversion-pairing” and “contingency degradation” were respectively utilized in Experiments 1 and 2 to determine if responding for each reward was goal-directed or habitual. Both tests were consistent in suggesting the training parameters employed produced goal-directed saccharin responding, but habitual nicotine responding. Particularly noteworthy is the exceptionally rapid rate at which nicotine-seeking habits appear to have developed. ii Acknowledgements I am the product of all of my relations, thus this work is not my own. Only through the generous support of all of the following people was this thesis made possible, and as such, I would like to offer my sincere gratitude to: Dr. AD Lê, for the wonderful mentorship which has expanded my thought, developed my character, and finally revealed to me the importance of discipline; Kathy Coen, for sharing with me her stunning brilliance in translating thought to action; Dr. Doug Funk, for frequent uplifts of spirit and assistance in thesis writing; Sahar Tamadon and Zhaoxia Li, for the support and company through long days of work; Dr. Paul Fletcher and my graduate education committee, for all the time and effort expended for the benefit of students like myself; James Ennis and Casey Suchit, for the helping hands and kind words, Jack Bilodeau, for reminding me to rock and roll, Abhiram Pushparaj, for being a friend both witty and wise, Jillian Burston, for the constant camaraderie I couldn’t have done without; Everyone else from CAMH and the University of Toronto I’ve had the privilege of knowing, for making this period of my life possible; Every scientist before me, for the shoulders upon which I hope to stand; And of course, my mother and father, for giving me life and more. Finally, I would like to express my profound appreciation for every subject who has contributed to this research. To you, I owe a debt which cannot be repaid. iii Table of Contents Abstract ................................................................................................................... ii Acknowledgements ............................................................................................. iii Table of Contents .................................................................................................. iv List of Figures ........................................................................................................... ix List of Tables ............................................................................................................. x CHAPTER 1: Introduction ....................................................................................... 1 1.1 Tobacco Use and Nicotine Addiction ................................................... 1 1.1.1 Statement of Problem .......................................................................... 1 1.1.2 Cigarettes and Nicotine ...................................................................... 1 1.1.3 Nicotine Pharmacokinetics ................................................................. 2 1.1.4 Nicotine Pharmacodynamics ............................................................. 4 1.2 Animal Models of Drug Reward and Reinforcement .......................... 6 1.2.1 Animal Models of Drug Reward ......................................................... 6 1.2.2 Animal Models of Drug Reinforcement ............................................. 9 1.3 Mechanisms of Nicotine Reward ......................................................... 12 1.3.1 The Mesolimbic Dopamine System ................................................. 12 1.3.2 Nicotine and the Mesolimbic Reward System .............................. 14 1.4 Theoretical Frameworks of Substance Dependence ....................... 15 1.4.1 Motivational Accounts of Substance Dependence.................... 15 1.4.2 Compulsive Accounts of Substance Dependence ..................... 17 iv 1.5 Habit ......................................................................................................... 20 1.5.1 Two-System Control of Instrumental Behavior ............................... 20 1.5.2 Goal-Directed Behaviors .................................................................. 23 1.5.3 Determinants of Habit Formation .................................................... 25 1.6 Distinguishing Goal-Directed and Habitual Behavior ....................... 29 1.6.1 Outcomes and Contingencies ........................................................ 29 1.6.2 Manipulations of Outcome Value .................................................. 29 1.6.3 Manipulations of Instrumental Contingency ................................. 34 1.7 The Effects of Drugs on Habits in Animal Models ............................... 37 1.7.1 Specific Acceleration of Habit Formation ..................................... 37 1.7.2 Generalized Acceleration of Habit Formation ............................. 38 1.7.3 Drugs and the Neural Substrates of Habit ...................................... 39 1.8 Habits, Addiction, and Nicotine ........................................................... 42 1.8.1 The Hijack of Habit ............................................................................. 42 1.8.2 Habits in Compulsive Drug Use ........................................................ 44 1.8.3 A Role for Habit in Nicotine Dependence? .................................. 45 CHAPTER 2: Purpose of Investigation ................................................................ 46 CHAPTER 3: General Materials and Methods ................................................. 48 3.1 Subjects .................................................................................................... 48 3.1.1 Animals & Housing ............................................................................. 48 3.2 Intravenous Jugular Vein Catheterization .......................................... 49 3.2.1 Catheter Construction ...................................................................... 49 v 3.2.2 Surgical Procedures ........................................................................... 50 3.3 Apparatus ................................................................................................ 55 3.3.1 General Procedures .......................................................................... 55 3.3.2 Orally Consumed Saccharin Self-Administration .......................... 58 3.3.3 Intravenous Nicotine Self-Administration ....................................... 59 3.3.4 Statistical Analysis .............................................................................. 61 CHAPTER 4: Experiment 1 - LiCl Devaluation of Intravenous Nicotine ........ 62 4.1 Experiment 1: Introduction .................................................................... 62 4.1.1 Aversion-Pairing to Nicotine ............................................................. 62 4.1.2 Experimental Objectives and Hypotheses .................................... 64 4.2 Experiment 1: Materials and Methods ................................................. 65 4.2.1 General Procedures .......................................................................... 65 4.2.2 Devaluation: LiCl-Reinforcer Pairing ............................................... 67 4.2.3 Experiment 1A: Pre-Acquisition Devaluation ................................. 70 4.2.4 Experiment 1B: Post-Acquisition Devaluation ................................ 71 4.3 Experiment 1: Results .............................................................................. 73 4.3.1 Experiment 1A: Pre-Acquisition Devaluation ................................. 73 4.3.2 Experiment 1B: Post-Acquisition Devaluation Results ................... 78 4.4 Experiment 1: Discussion ........................................................................ 96 4.4.1 LiCl and Saccharin ............................................................................ 96 4.4.2 LiCl and Nicotine ............................................................................... 98 4.4.3 Conclusions ....................................................................................... 100 vi CHAPTER 5: Experiment 2 - Contingency Degradation .............................. 101 5.1 Experiment 2: Introduction .................................................................. 101 5.1.1 Assessing Sensitivity to Instrumental Contingency ...................... 101 5.2 Experiment 2: Materials and Methods ............................................... 104 5.2.1