This page intentionally left blank Imaging Dopamine Since its discovery 50 years ago, brain dopamine has been implicated in the control of movement and cognition, and has emerged as a key factor in diverse brain diseases such as Parkinson’s disease, schizophrenia, and drug addiction. This book is an illustrated biography of the dopamine molecule, beginning with an account of its synthesis in brain, and then describing its storage, release and signalling mechanisms, and its ultimate metabolic breakdown. Using color illustrations of positron emission tomography (PET) scans, each chapter presents a specific stage in the biochemical pathway for dopamine. Writing for researchers and graduate students, Paul Cumming presents an overview of all that has been learned about dopamine through molecular imaging, a technology which allows the measurement of formerly invisible processes in the living brain. He reviews current technical controversies in the interpretation of dopamine imaging and presents key results illuminating the roles of brain dopamine in illness and health. Paul Cumming is Professor in the Department of Nuclear Medicine at Ludwig- Maximilian University in Munich, Germany. He currently serves on the editorial boards of the journals Synapse, Journal of Cerebral Blood Flow and Metabolism, and NeuroImage. Imaging Dopamine PAUL CUMMING Ludwig-Maximilian University, Munich, Germany CAMBRIDGE UNIVERSITY PRESS Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521790024 © P. Cumming 2009 This publication is in copyright. Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published in print format 2009 ISBN-13 978-0-511-53339-6 eBook (EBL) ISBN-13 978-0-521-79002-4 hardback Cambridge University Press has no responsibility for the persistence or accuracy of urls for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. “But as if a magic lantern threw the nerves in patterns on a screen.” T. S. Eliot To the remembrance of Professor George Leslie Cumming (1930–1994) Contents Foreword xiii Acknowledgments xv Introduction 1 1. The life history of dopamine 5 1.1. A brief overview of the dopamine pathway 5 1.2. A brief account of the blood–brain barrier 10 1.3. Neurochemical anatomy of the nigrostriatal pathway 11 1.4. Physiology of dopamine neurons 15 1.5. The post-synaptic effects of dopamine 16 1.6. A brief introduction to molecular imaging 17 2. Enzymology of tyrosine hydroxylase 19 2.1. Molecular biology and enzymology 19 2.2. Disorders of tyrosine hydroxylase 20 2.3. Regulation of activity 22 2.4. Autoreceptor modulation of activity 24 2.5. Phosphorylation of tyrosine hydroxylase 25 2.6. Transcriptional regulation 27 3. The assay of tyrosine hydroxylase 29 3.1. Accumulation of DOPA after treatment with NSD 1015 29 3.2. Superfusion of living striatum with [3H]tyrosine 34 3.3. Intracerebroventricular infusion of [3H]tyrosine 36 3.4. Intravenous injection of [3H]tyrosine 36 3.5. Modeling the metabolism of [3H]tyrosine 37 3.6. Autoradiography in vivo with tyrosine: an introduction to the analysis of PET data 40 ix x Contents 4. Enzymology of aromatic amino acid decarboxylase 45 4.1. Kinetic properties of AAADC in vitro 45 4.2. Regulation and transcription of AAADC 48 4.3. AAADC activity in living brain 50 4.4. In vivo metabolism of AAADC substrates 51 5. PET studies of DOPA utilization 54 5.1. General aspects of the quantitation of FDOPA utilization 54 5.2. Methods for the quantitation of DOPA-PET studies 57 5.3. The true activity of AAADC in living brain 67 5.4. Other substrates for PET studies of AAADC 68 5.5. Pharmacological modulation of AAADC activity 69 5.6. Clinical FDOPA-PET studies 71 5.7. Personality and cognition 77 6. Conjugation and sulfonation of dopamine and its metabolites 80 6.1. Biochemistry of COMT 80 6.2. Behavioral correlates of COMT activity 82 6.3. Arylsulfotransferase 83 7. Dopamine synthesis and metabolism rates 85 7.1. Steady-state and the epistemology of dopamine metabolism 85 7.2. Turnover of dopamine 86 7.3. Turnover of the acidic metabolites 89 7.4. 3-Methoxytyramine 95 8. MAO activity in the brain 99 8.1. Enzymology 99 8.2. Neurochemical anatomy of MAO 101 8.3. Effects of MAO inhibition and knockout on dopamine transmission 102 8.4. Disorders of MAO and knockouts 103 8.5. MAO activity in vivo 104 8.6. Clinical PET studies of MAO 109 9. Vesicular storage of dopamine 111 9.1. Biochemistry of vesicular monoamine transporters 111 9.2. Chromaffin granules 112 Contents xi 9.3. Regulating and knocking out VMAT2 114 9.4. Ligands and tracers for VMAT2 115 9.5. Clinical PET studies of VAT2 120 10. Dopamine release: from vesicles to behavior 122 10.1. Methods for measuring dopamine release 122 10.2. Concentration gradients for dopamine across the plasma membrane 127 10.3. The action of psychostimulants 128 10.4. Behavioral correlates of dopamine release 131 11. The plasma membrane dopamine transporter 137 11.1. Molecular biology of DAT and regulation of expression 137 11.2. Functional aspects of DAT, and how to live without it 138 11.3. Ligands for the detection of DAT 141 11.4. Clinical DAT studies 149 12. Dopamine receptors 160 12.1. Pharmacology and biochemistry 160 12.2. Neurochemical anatomy 161 12.3. Dopamine receptor signal transduction 163 12.4. Agonist-induced internalization of dopamine receptors 165 13. Imaging dopamine D1 receptors 167 13.1. General aspects of D1 receptors 167 13.2. PET ligands for D1 receptors 168 13.3. Imaging studies of D1 receptors 171 14. Imaging dopamine D2 receptors 174 14.1. General properties of D2 ligands 174 14.2. Oligomeric associations of dopamine D2 receptors 180 14.3. Effects of denervation on D2 receptors 181 14.4. Competitive binding at D2 receptors in living brain 182 14.5. Clinical studies of dopamine D2 receptors 194 15. Factors influencing D2 binding in living brain 203 15.1. Pharmacological modulation 203 15.2. Clinical studies of psychostimulant-evoked dopamine release 205 15.3. Other pharmacological challenges altering dopamine receptor binding 212 xii Contents 15.4. Transcranial magnetic stimulation, deep brain stimulation, and sensory stimulation 215 15.5. Personality 217 15.6. Pain and stress 218 15.7. Motivation, craving, and placebo 220 16. The absolute abundance of dopamine receptors in the brain 224 17. Conclusions and perspectives 229 References 234 Index 331 The col or plates ar e betw een pages 28 and 29, and pages 224 and 225. Foreword This book is timely and will prove useful for many researchers interested not only in the specific topic, “Imaging Dopamine,” but also in more general aspects of dopamine. In neurotransmitter research, dopamine has served a spearhead function ever since its discovery in the brain half a century ago. Dopamine has also played a key role in molecular imaging research; the imaging of dopamine receptors started very early in the history of positron emission tomography. Although this book has its focus on imaging, the full utilization of imaging techniques depends on the background knowledge gained from other methodo- logies, a theme that has been duly considered by the author. Thus, the various aspects of dopamine, dealing, for example, with its synthesis, storage, release, and metabolism, as well as with the enzymes and transporter proteins involved in these processes, are treated in sufficient detail to provide a well-integrated and reasonably complete picture of the very complex dopamine transmission machinery. It should go without saying that the growth of knowledge regarding the various aspects of neurotransmission has not taken place without intervals of considerable disagreement and controversy. In the course of the past half century’s intense research, many issues have been resolved, whereas others are still being debated. I am pleased to find that the author has devoted some space to historical aspects, starting out with a scheme of the dopamine nerve terminal published by me in 1966. Indeed, our first experiments made in 1957 and the following years initially led to a considerable controversy, based largely on the belief prevailing at the time that the nerve cells in the brain communicated mainly by electric signaling. Thus, our proposal that the cate- cholamines dopamine and noradrenaline served important neurotransmitter functions in the brain was at the time hard to accept by most leaders in the field. This was evident at an international meeting in London in 1960. But only five years later, at a subsequent international meeting in Stockholm, the concept of xiii xiv Foreword chemical transmission in the brain had already gained considerable acceptance. This was largely due to the development of histochemical techniques, by means of which Swedish research groups had been able to visualize the neuronal localization of monoamines in the central nervous system, thus providing further evidence of their neurotransmitter function. However, very soon other controversies followed. For example, there arose a debate on whether synaptic vesicles were essential in the physiological release process or were just serving as “garbage cans.” Since those early days, the field of dopamine research has moved a long way, largely thanks to the advent of an array of powerful techniques. The early pharmacological work proposing the existence of several subtypes of dopamine receptors, “autoreceptors,” and transporter proteins could be confirmed by molecular biology techniques, and their roles further elucidated by, for exam- ple, knockout techniques.