Behavioural and Pharmacological Interactions Between Drug and Nutritional Reinforcers
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` Behavioural and Pharmacological Interactions between Drug and Nutritional Reinforcers By Meenu Minhas A Thesis Presented to The University of Guelph In partial fulfillment of requirements For the degree of Doctor of Philosophy in Psychology Guelph, Ontario, Canada © Meenu Minhas, August, 2018 ABSTRACT BEHAVIOURAL AND PHARMACOLOGICAL INTERACTIONS BETWEEN DRUG AND NUTRITIONAL REINFORCERS Meenu Minhas Advisor: University of Guelph, 2018 Dr. Francesco Leri The repeated consumption of highly palatable food shares several behavioural and neurobiological similarities with drugs of abuse. This has led to the “food addiction” hypothesis which predicts that highly palatable food can promote “addictive” behaviours. This hypothesis predicts that sugar and drug reinforcers should interact to influence responses to each other, and that the behaviours engendered by these reinforcers should be comparable in situations where their availability is similar. The studies in this dissertation were designed to test these predictions in male Sprague-Dawley rats using high fructose corn syrup (HFCS) and oxycodone (OXY). HFCS was selected because it is a widely used added sugar in our diets and OXY was selected because it is a widely used and abused prescription opioid. Study 1 explored the effect of a HFCS-rich diet on behavioural and neurochemical responses to OXY. It was found that HFCS decreased OXY-induced locomotion and OXY- induced dopamine release in the nucleus accumbens but did not alter OXY conditioned place preference. Study 2 investigated interactions between HFCS and OXY on taking and seeking behaviors in the same subject using the innovative procedure of co-self-administration of intraoral (IO) HFCS and intravenous (IV) OXY. It was found that OXY and HFCS differentially controlled seeking expressed by the same subjects: OXY engenders more persistent behaviour than HFCS, both in the presence and absence of stimuli predicting their availability. Study 3 investigated how a pharmacotherapy used to treat obesity and drug craving could affect HFCS and OXY seeking in animals trained to self-administer both. It was found that acute bupropion increased the magnitude of cue reinstatement for both OXY and HFCS-paired levers, and that the magnitude of the increase was larger for OXY. Collectively, these studies demonstrate that opioid and sugar reinforcers act on similar systems of learning and reinforcement, although there are differences in the extent to which these systems appear engaged. This said, these reinforcers can affect responses to each other, and this suggests that nutrition can play a significant role in the development and maintenance of drug addiction. iv ACKNOWLEDGEMENTS Over the years in conducting my research and preparing my thesis, I have received an incredible amount of support and guidance from several individuals, without whom this PhD would not have been possible. First and foremost, I would like to thank my advisor, Dr. Francesco Leri for his continuous support and guidance while pursuing my PhD. As I look back on the skills that I have developed as an academic, I realize that I could not have come as far as I have, without his guidance, trust, and drive to push me towards the potential that he saw in me. My time in the lab was the most significant developmental period for me; and has afforded me critical thinking, communication, and analytic skills that will undoubtedly help me as I move onto the next stage of my life. I would also like to thank my committee members, Dr. Linda Parker, Dr. Naseem Al- Aidroos, and Dr. Paul Mallet for your time, support, guidance, and insight over the years. Thank you for providing thoughtful feedback and discussions. To Dr. Cheryl Limebeer who not only taught me microdialysis, but also quantified all my samples (and there were a lot!); that data would have not been possible without you! Also, thank you for always helping when I needed something or colossally screwed something up and needed guidance. We might not always say it, but all your input, and help over the years has been much appreciated. I would also like to thank Robin Sorbara, for always being willing to help, guide, and generally just make the lives of all the graduate students easier, we would be lost without you! Next, I would like to thank the NACS graduate students, past and current members of the Leri Lab for making the last few years an enjoyable experience. A special thanks in particular goes to v AnneMarie Levy, Kelsy Ervin, Krista Mitchnick, Samantha Creighton, Daniel Palmer and Richard Matta, you have become great friends without whom graduate school would be a lot harder. Your confidence in my abilities, when my own were wavering, and providing an environment that was comfortable and collaborative has been paramount in helping me get through my PhD. I am not sure I could have made it without your support! Lastly, I must thank my parents for the support provided throughout the years. I have always admired the hard work ethic of both my parents. It has allowed me to develop a strong work ethic of my own and has shaped my attitude in ways that has allowed me to get as far as I am today. vi TABLE OF CONTENTS Abstract……………………………………………………………………………………………ii Acknowledgments………………………………………………………………………………..iv Table of Contents………………………………………………………………………………....vi List of Tables………………………………………………………………………………….….ix List of Figures………………………………………………………………………...…………...x List of Abbreviations………………………………………………………………………..…...xii Statement of Research Problem…………………………………………………………………xiii Main Research Objectives………………………………………………...……………………. xv Chapter 1: General Introduction 1.1. Food Addiction…………………………………………………………………...…..2 1.2. Animal Models of Food Addiction...……………………………………………........4 1.3. Assessment of responses to drugs of abuse and palatable food ……………………...6 1.3.1. Conditioned Place Preference...…….……………….………………….......6 1.3.2. Drug-taking...…….……………….…………………………………….......7 1.3.3. Drug-seeking……….……………….………………………………………9 1.3.4. Locomotor sensitization……….……………….…….…………………....10 1.4. Similarities between drugs of abuse and highly palatable food…………………..…11 1.4.1. Human……………………………………………………………………..11 1.4.1.1. Behavioural…….………………………………………………..11 1.4.1.2. Neurobiological……….……………….………………………...12 1.4.2. Animal………………………………………………………..……..……..13 1.4.2.1. Behavioural……….……………….………………..….…..……13 1.4.2.2. Neurobiological……………….…………………………………15 1.4.3. Drug and food interactions………………………………………………...15 1.4.3.1. Humans……….……………….…………………………..…….15 1.4.3.2. Animals……….……………….………………………………...16 1.5. Differences between drugs of abuse and highly palatable food…………………….18 1.5.1. Behavioural……….……………….…………………………………...….18 1.5.2. Neurobiological……….……………….…………………………………..19 1.6. Reward Processing by the Opioid System……….……………….………...…….…22 1.7. The Role of Dopamine……….……………….……………………………………..24 1.8. Neurobiology of food intake………………………………………………………...26 1.8.1. Orosensory……….……………….……………………………………….27 1.8.2. Post-ingestive……….……………….…………………………………….28 1.9. High Fructose Corn Syrup……….……………….……………………………..…..29 1.10. Oxycodone…………………………………………………………………………33 1.11. Rationale and objectives…………………………………………………………...37 Chapter 2: The effect of chronic high fructose corn syrup on oxycodone induced conditioned approach, locomotion, and dopamine release in the nucleus accumbens 2.1. Abstract……….……………….…………………………………………………….41 2.2. Introduction………………………………………………………………………….43 2.3. Methods and materials……………………………………………………………....45 2.3.1. Subjects…………………………………………………………………....45 2.3.2. Apparatus………………………………………………………………….46 2.3.2.1. Home-cage self-administration ………………………………....46 vii 2.3.2.2. Conditioned place preference …………………………………..46 2.3.2.3. Locomotion……………………………………………………...47 2.3.2.4. Microdialysis ……………………………………………………47 2.3.3. Surgical procedures………………………………………………………..48 2.3.4. General procedures………………………………………………………..48 2.3.4.1. Pre-exposure…………………………………………………….48 2.3.4.2. Experiment 1: Place conditioning ………………………………49 2.3.4.3. Experiment 2: Locomotor testing ………………………………50 2.3.4.4. Experiment 3: Microdialysis….…………………………………51 2.3.5. Histology …………………………… …………………………………....52 2.3.6. Drugs and High Fructose Corn Syrup……………………………………..52 2.3.7. Statistical analyses………………………………………………………...52 2.4. Results……………………………………………………………………………….53 2.4.1. Home cage consumption…………………………………………………..53 2.4.2. Experiment 1: Place conditioning…………………………………………53 2.4.3. Experiment 2: The effect of HFCS exposure on OXY-induced locomotion….……………………………………………………………..54 2.4.4. Experiment 3: Microdialysis………….…………………………………...56 2.5. Discussion…………………………………………………………………………...56 2.6. Conclusion…………………………………………………………………………..61 Chapter 3: Dual self-administration of oxycodone and high fructose corn syrup in rats 3.1. Abstract……………………………………………………………………………...72 3.2. Introduction………………………………………………………………………….74 3.3. Methods and Materials………………………………………………………………76 3.3.1. Subjects……………………………………………………………………76 3.3.2. Apparatus………………………………………………………………….77 3.3.3 Intravenous and intra-oral surgery…………………………………………77 3.3.4. General procedures………………………………………………………..77 3.3.4.1. Experiment 1: Single self-administration……………………….77 3.3.4.2. Experiment 2: Dual self-administration………………………....79 3.4. Drugs and food………………………...……………….…………………………....80 3.5. Statistical Analyses……………….……….……………….………………………..81 3.6. Results……………….……….……………….……………………………………..84 3.6.1. Exclusion criteria…………………….. …………………………………..84 3.6.2. Experiment 1-Single self-administration………………………………….84 3.6.3. Experiment 2-Dual Self-administration……………………...…………....88