Imaging Dopamine Book

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

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

6Conjugation 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

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

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