THE INFLUENCE OF CATECHOLAMINES ON WORKING MEMORY AND THE ACTIVATIONAL ASPECTS OF MOTIVATION by Mavis Kusi A thesis submitted to the Centre for Neuroscience Studies In conformity with the requirements for the degree of Doctor of Philosophy Queen’s University Kingston, Ontario, Canada (July, 2020) Copyright © Mavis Kusi, 2020 Abstract Catecholamines are thought to have a major modulatory effect on cognition. However, there is only equivocal evidence that catecholamines have a direct impact on cognition. A body of research suggests that catecholamines influence motivation, through which they may have an indirect effect on cognition. Theories of motivation distinguish directional (behaviour toward or away from some stimuli) and activational aspects of motivation. The activational aspects of motivation (or behavioural activation) refer to the quantitative and qualitative features of motivated behaviour (speed, vigour and persistence) that enable organisms to overcome constraints that prevent them from obtaining a motivational stimulus. Here we investigated the contribution of catecholamines to cognition (using working memory as a cognitive model; working memory is a limited-capacity cognitive process that temporarily retains relevant information to guide thoughts and actions) and behavioural activation by augmenting catecholamine neurotransmission using the catecholamine reuptake inhibitors methylphenidate (MPH; 0.1-10 mg/kg) and atomoxetine (ATX; 0.01-1.0 mg/kg) in adult female Chinese rhesus macaques (Macaca mulatta). We also tested the effects of diminishing catecholamine neurotransmission on working memory and behavioural activation using an acute tyrosine phenylalanine depletion (ATPD) method, which we developed and demonstrated its effectiveness at impairing brain catecholamine synthesis and function. A visual sequential comparison (VSC) task, which allows the systematic manipulation of working memory load was used to assess working memory. Behavioural activation was assessed using several measures: the animals’ reaction time (speed), saccade peak velocity (vigour), successful trial completion (persistence), successful trial initiation (persistence), trial initiation time (speed), and anticipatory trial initiation (vigour) in the VSC task. A visual progressive ratio (PR) schedule of reinforcement task was also used to assess behavioural activation; the PR breakpoint reflects persistence. The results of the MPH, ATX and ATPD studies showed that catecholamines have little to no impact on working memory but a significant influence on behavioural activation. ii Co-Authorship I was the primary researcher involved in the planning and design of the research projects within this thesis. I was also the primary experimenter involved in the acquisition, analysis and interpretation of the research data presented in this thesis and the primary writer of the material presented here. Dr. Martin Paré supervised these research projects and contributed to the conception and design of the projects as well as the analyses and interpretation of the data. I received assistance with data collection from Catherine Crandell and Brittney Armitage-Brown who are research assistants for the lab. iii Acknowledgements I would like to thank my supervisor, Dr. Martin Paré for giving me the opportunity to do this research in his lab. Thank you for your support and guidance throughout these research projects. I have learned a lot from you about neuroscience experimentation, scientific writing, critical analysis of research data, data visualization, and so much more. Thank you for being a great supervisor. I am very grateful for all of the help that you gave me throughout the course of my PhD studies. I would also like to thank the past and present members of the Paré lab, particularly Catherine Crandell, Brittney Armitage-Brown, Lindsey Thurston, and Pranavan Thirunavukkarasu for your assistance, advice and engaging conversations during the course of my PhD studies. My sincerest gratitude to Catherine Crandell and Brittney Armitage-Brown for their support, hard work and dedication to these projects. Thank you for teaching me how to work with the animals and for all of your help with data collection, especially with the ATPD experiments which involved a lot of work and early mornings in the lab. These projects would not have been possible without your assistance. Thank you to the members of the Centre for Neuroscience Studies for their support and guidance throughout the course of my PhD studies. I would also like to thank the Queen’s veterinary and animal care staff for their assistance with animal care and training. Many thanks to Dr. Andrew Winterborn for his help with blood and CSF sampling. Thank you to Emma Robertson for helping me with plasma and CSF sampling. Emma, I am very grateful to you for teaching me how to pipette and for always taking time out of your day to help me with my samples. Lastly, I want to thank my family, my boyfriend, Jason Lane and my friends for their continual support and encouragement. Thank you for being there to listen and for always cheering me on. iv Table of Contents Abstract ......................................................................................................................................................... ii Co-Authorship.............................................................................................................................................. iii Acknowledgements ...................................................................................................................................... iv List of Figures ............................................................................................................................................... x List of Tables .............................................................................................................................................. xii List of Abbreviations ................................................................................................................................. xiii Chapter 1 General Introduction .................................................................................................................... 1 1.1 Working Memory ............................................................................................................................... 2 1.1.1 What is Working Memory? .......................................................................................................... 2 1.1.2 Neural Basis of Working Memory ............................................................................................... 4 1.1.2.1 Persistent Activity ............................................................................................................... 5 1.1.2.2 Catecholamine Modulation of Working Memory ............................................................... 7 1.1.2.2.1 Dopamine and Working Memory .......................................................................... 8 1.1.2.2.2 Norepinephrine and Working Memory ................................................................ 12 1.2 Motivation ........................................................................................................................................ 16 1.2.1 What is Motivation? ................................................................................................................... 16 1.2.2 Tasks Used to Study Behavioural Activation ............................................................................ 17 1.2.3 The Role of Dopamine in Behavioural Activation .................................................................... 23 1.2.4 The Role of Norepinephrine in Behavioural Activation ............................................................ 28 1.3 Scope of this Research ..................................................................................................................... 29 1.4 References ........................................................................................................................................ 31 1.5 Figures .............................................................................................................................................. 44 Chapter 2 The Effects of Methylphenidate on Behaviour and Cognition in Rhesus Monkeys ................. 45 2.1 Abstract ............................................................................................................................................ 46 2.2 Introduction ...................................................................................................................................... 47 2.2.1 Methylphenidate and Working Memory .................................................................................... 49 2.2.2 Methylphenidate and Motivation ............................................................................................... 49 2.2.3 Methylphenidate and Psychotomimetic, General and Social Behaviours .................................. 51 2.2.4 Study Aims and Hypotheses ...................................................................................................... 51 2.3 Materials and Methods ..................................................................................................................... 52 2.3.1 Subjects ...................................................................................................................................... 52 2.3.2 Apparatus ..................................................................................................................................