Imaging dopamine

Cover......Page 1
Half-title......Page 3
Title......Page 5
Copyright......Page 6
Dedication......Page 9
Contents......Page 11
Foreword......Page 15
Acknowledgments......Page 17
Introduction......Page 19
1.1 A brief overview of the dopamine pathway......Page 23
1.2 A brief account of the blood–brain barrier......Page 28
1.3 Neurochemical anatomy of the nigrostriatal pathway......Page 29
1.4 Physiology of dopamine neurons......Page 33
1.5 The post-synaptic effects of dopamine......Page 34
1.6 A brief introduction to molecular imaging......Page 35
2.1 Molecular biology and enzymology......Page 37
2.2 Disorders of tyrosine hydroxylase......Page 38
2.3 Regulation of activity......Page 40
2.4 Autoreceptor modulation of activity......Page 42
2.5 Phosphorylation of tyrosine hydroxylase......Page 43
2.6 Transcriptional regulation......Page 45
3.1.1 General aspects......Page 55
3.1.2 Caveats of the NSD 1015 method......Page 57
3.1.3 Regulation of DOPA synthesis by autoreceptors......Page 58
3.1.4 Other factors regulating DOPA synthesis......Page 59
3.2 Superfusion of living striatum with [3H]tyrosine......Page 60
3.4 Intravenous injection of [3H]tyrosine......Page 62
3.5 Modeling the metabolism of [3H]tyrosine......Page 63
3.6 Autoradiography in vivo with tyrosine: an introduction to the analysis of PET data......Page 66
4.1 Kinetic properties of AAADC in vitro......Page 71
4.2 Regulation and transcription of AAADC......Page 74
4.3 AAADC activity in living brain......Page 76
4.4 In vivo metabolism of AAADC substrates......Page 77
5.1 General aspects of the quantitation of FDOPA utilization......Page 80
5.2.1 The reference tissue method......Page 83
5.2.3 Compartmental analysis......Page 84
5.2.4 Steady-state estimates of FDOPA kinetics......Page 90
5.3 The true activity of AAADC in living brain......Page 93
5.4 Other substrates for PET studies of AAADC......Page 94
5.5 Pharmacological modulation of AAADC activity......Page 95
5.6.1 Age-related changes measured by FDOPA-PET......Page 97
5.6.2 Acquired parkinsonism and idiopathic Parkinson’s disease......Page 98
5.6.3 Other clinical FDOPA studies......Page 101
5.7 Personality and cognition......Page 103
6.1 Biochemistry of COMT......Page 106
6.2 Behavioral correlates of COMT activity......Page 108
6.3 Arylsulfotransferase......Page 109
7.1 Steady-state and the epistemology of dopamine metabolism......Page 111
7.2 Turnover of dopamine......Page 112
7.3.1 Transport mechanisms......Page 115
7.3.2 Efflux of acidic metabolites from brain......Page 116
7.3.3 Conjugation of acidic metabolites......Page 118
7.3.4 Cerebrospinal fluid metabolites......Page 120
7.4.2 Blockade of 3MT synthesis and metabolism......Page 121
8.1 Enzymology......Page 125
8.2 Neurochemical anatomy of MAO......Page 127
8.3 Effects of MAO inhibition and knockout on dopamine transmission......Page 128
8.4 Disorders of MAO and knockouts......Page 129
8.5.1 Irreversible MAO ligands......Page 130
8.5.2 Reversible MAO ligands......Page 132
8.6 Clinical PET studies of MAO......Page 135
9.1 Biochemistry of vesicular monoamine transporters......Page 137
9.2.1 Biochemical properties......Page 138
9.3 Regulating and knocking out VMAT2......Page 140
9.4 Ligands and tracers for VMAT2......Page 141
9.5 Clinical PET studies of VAT2......Page 146
10.1.1 HPLC with electrochemical detection......Page 148
10.1.3 Cerebral microdialysis......Page 149
10.1.4 In vivo electrochemistry......Page 151
10.2 Concentration gradients for dopamine across the plasma membrane......Page 153
10.3.1 Amphetamines......Page 154
10.3.4 Other pharmacological factors......Page 156
10.4.1 Ordinary movement......Page 157
10.4.2 Turning......Page 158
10.4.3 Appetitive behaviors......Page 160
10.4.4 Stress......Page 161
11.1 Molecular biology of DAT and regulation of expression......Page 163
11.2 Functional aspects of DAT, and how to live without it......Page 164
11.3.1 Tropanes......Page 167
11.3.2 Other DAT ligands......Page 173
11.3.3 Competition in living brain......Page 174
11.4.1 Aging and genetics......Page 175
11.4.2 Parkinson’s disease......Page 178
11.4.3 Other neuropsychiatric disorders......Page 180
11.4.4 Drug abuse......Page 183
11.4.5 Psychostimulant action and euphoria......Page 184
12.1 Pharmacology and biochemistry......Page 186
12.2 Neurochemical anatomy......Page 187
12.3 Dopamine receptor signal transduction......Page 189
12.4 Agonist-induced internalization of dopamine receptors......Page 191
13.1 General aspects of D1 receptors......Page 193
13.2 PET ligands for D1 receptors......Page 194
13.3.1 Clinical studies......Page 197
13.3.2 Competition at D1 sites in living brain......Page 199
14.1.1 Irreversible ligands......Page 200
14.1.2 Reversible binding of benzamides......Page 201
14.1.3 D2 agonist binding sites in the brain......Page 204
14.2 Oligomeric associations of dopamine D2 receptors......Page 206
14.3 Effects of denervation on D2 receptors......Page 207
14.4.1 Benzamide antagonists......Page 208
14.4.2 Butyrophenone antagonists......Page 211
14.4.3 Agonists......Page 215
14.5.1 Aging and genetics......Page 220
14.5.2 Neurological disorders......Page 223
14.5.3 Psychiatric disorders......Page 224
14.5.4 Receptor occupancy during treatment with antipsychotic medication......Page 226
14.5.5 Receptor occupancy by agonists......Page 228
15.1.1 Dopamine antagonists......Page 229
15.1.3 Drugs of abuse......Page 230
15.2.1 Schizophrenia spectrum disorders......Page 231
15.2.2 Other psychiatric disorders and substance abuse......Page 234
15.2.3 Parkinson’s disease......Page 237
15.3.1 Nicotine, smoking, and caffeine......Page 238
15.3.3 Others......Page 239
15.4 Transcranial magnetic stimulation, deep brain stimulation, and sensory stimulation......Page 241
15.5 Personality......Page 243
15.6 Pain and stress......Page 244
15.7 Motivation, craving, and placebo......Page 246
16 The absolute abundance of dopamine receptors in the brain......Page 250
17 Conclusions and perspectives......Page 267
References......Page 272
Index......Page 369