UNIVERSITY OF CALIFORNIA Los Angeles Striatal Dopamine Receptors, Inhibitory Control and Methamphetamine Use Disorder A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Molecular and Medical Pharmacology by Chelsea Robertson 2015 © Copyright by Chelsea Robertson 2015 ABSTRACT OF THE DISSERTATION Striatal Dopamine Receptors, Inhibitory Control and Methamphetamine Use Disorder by Chelsea Robertson Doctor of Philosophy in Molecular and Medical Pharmacology University of California, Los Angeles, 2015 Professor Edythe D. London, Chair Inhibitory control is a neurocognitive construct that describes the capacity to exert control over behaviors, thoughts, actions and emotions. It is essential to everyday life and is an important component of executive function necessary for goal directed behavior. However, deficits in inhibitory control are manifested across several neuropsychiatric disorders, especially substance use disorders. Although the neurobiological mechanisms that underlie human inhibitory control are not completely clear, neuroimaging studies have advanced our understanding of the underlying circuitry of inhibitory control and pharmacological studies have highlighted an essential role for dopaminergic neurotransmission. However, there remains much to be understood about how different striatal dopaminergic receptor systems influence inhibitory control capacity. Therefore, the research in this dissertation aims to increase our understanding of how striatal ! ii dopaminergic signaling at different dopamine receptor subtypes (D1- and D2-type) contributes to individual levels of impulsivity and inhibitory control. Dopaminergic deficiencies in stimulant use disorder are linked to several clinically relevant indices, including treatment retention and outcomes. Dopamine markers are associated with behaviors and cognitive functions important to the development and maintenance of addiction, including inhibitory control, risk-taking and delay of gratification. Therefore, augmenting dopaminergic function is an attractive therapeutic target in the treatment of stimulant use disorders. However, the lack of approved pharmacological agents for this purpose has spurred an interest in alternative approaches to augmenting the dopaminergic signaling in stimulant users. On the basis of a large animal literature, aerobic exercise has been suggested as a mechanism to increase dopamine system function in stimulant use disorder. Research in this dissertation aims to determine the effects of exercise on the dopamine system in individuals with methamphetamine use disorder. Determining the relevance of individual variation in dopaminergic markers on human behavior will improve our understanding of the molecular basis of inhibitory control and its dysregulation in substance use disorders. Furthermore, investigating methods to improve dopamine function in individuals with methamphetamine use disorder represents an important step for improving addiction treatment. ! iii This dissertation of Chelsea Robertson is approved. James David Jentsch Daniel H. Silverman Richard W. Olsen Heather R. Christofk Edythe D. London, Committee Chair University of California, Los Angeles 2015 ! iv To my family and friends… Your endless love, support and encouragement were integral to this work. Without it, this dissertation would not have been possible. Thank you. ! v TABLE OF CONTENTS ABSTRACT OF THE DISSERTATION ..................................................................................... ii LIST OF FIGURES & TABLES ................................................................................................ vii ACKNOWLEDGEMENTS .......................................................................................................... ix CURRICULUM VITAE ................................................................................................................ x CHAPTER 1: INTRODUCTION ................................................................................................. 1 METHAMPHETAMINE USE: A GLOBAL HEALTH PROBLEM ........................................................... 2 PHARMACOLOGY OF METHAMPHETAMINE .................................................................................. 3 Mechanism of action ................................................................................................................. 3 Neurotoxicity ............................................................................................................................. 4 Pharmacokinetics ...................................................................................................................... 5 Behavioral and physiological effects in humans ...................................................................... 6 METHAMPHETAMINE USE DISORDER ........................................................................................... 7 Neurobiological features .......................................................................................................... 7 Treatment options and correlates of therapeutic success ....................................................... 11 INHIBITORY CONTROL AND IMPULSIVITY .................................................................................. 14 Inhibitory control in methamphetamine use disorder ............................................................. 14 Types of inhibition ................................................................................................................... 15 Striatal dopamine signaling .................................................................................................... 17 The role of dopaminergic neurotransmission ......................................................................... 18 SUMMARY OF THE DISSERTATION RESEARCH PROJECT ........................................ 20 CHAPTER 2: ASSOCIATION OF STRIATAL D1- & D2-TYPE DOPAMINE RECEPTORS WITH MOTOR RESPONSE INHIBITION ............................................................................. 43 INTRODUCTION ........................................................................................................................... 45 METHODS .................................................................................................................................... 47 RESULTS ...................................................................................................................................... 53 DISCUSSION ................................................................................................................................ 56 FIGURES & TABLES ..................................................................................................................... 62 CHAPTER 3: PERSONALITY SCALES OF IMPULSIVITY: RELATIONSHIP TO D1- AND D2 RECEPTORS ......................................................................................................... 80 INTRODUCTION ........................................................................................................................... 81 METHODS .................................................................................................................................... 83 RESULTS ...................................................................................................................................... 88 DISCUSSION ................................................................................................................................ 89 FIGURES & TABLES ..................................................................................................................... 93 CHAPTER 4: EFFECT OF EXERCISE TRAINING ON STRIATAL DOPAMINE D2/D3 RECEPTORS IN METHAMPHETAMINE USERS .............................................................. 104 INTRODUCTION ......................................................................................................................... 106 METHODS .................................................................................................................................. 108 RESULTS .................................................................................................................................... 113 DISCUSSION .............................................................................................................................. 116 FIGURES & TABLES ................................................................................................................... 123 CHAPTER 5: SUMMARY, DISCUSSION AND FUTURE DIRECTIONS ........................ 140 ! vi LIST OF FIGURES FIGURE 1.1 ...................................................................................................................... 4 Molecular structures of methamphetamine, amphetamine and endogenous brain monoamines. FIGURE 2.1 .................................................................................................................... 62 Scatter plot depicting the correlation between stop-signal reaction time (SSRT), and D1- type receptor binding potential (D1-type BPND) in the whole striatum. Table insert displays partial correlation coefficients, p values and R2 for the relationship between whole striatum and associative striatum D1-type BPND and SSRT, controlling for age and sex. FIGURE 2.2 .................................................................................................................... 63 Scatter plot depicting the correlation between stop-signal reaction