Neurokinetics (eBook)

Preface 6
Contents 14
1 Introduction to Compartmental Analysis 18
1.1 Concept of Compartments 18
1.1.1 Living Systems 18
1.1.2 Thermodynamics and Entropy 20
1.1.3 Fundamental Solution 23
1.1.4 Limitations of Compartmental Analysis 23
1.2 Single Tissue Compartment Analysis 24
1.3 Two Tissue Compartment Analysis 26
1.3.1 Compartmental Assumptions 26
1.3.2 Combined Compartments 29
1.3.3 Arteries and Veins 30
1.4 Three Tissue Compartment Analysis 31
1.4.1 Compartmental Assumptions 32
1.4.2 Combined Compartments 37
2 Fundamentals of Compartmental Kinetics 40
2.1 Definition of Relaxation Constants 40
2.1.1 Single Compartment 41
2.1.2 Two Compartments 42
2.1.3 Two Compartments with Sink 45
2.1.4 Three Compartments 47
2.1.5 Three Compartments with Sink 51
2.1.6 Four or More Compartments 53
2.1.7 Multiple Compartments in Series and in Parallel 56
2.2 Interpretation of Relaxation Constants 59
2.2.1 Flow 59
2.2.2 Passive Diffusion 60
2.2.3 Properties of Delivery Compartment 66
2.2.4 Protein--Ligand Interaction 73
2.2.5 Receptor Binding 78
2.2.6 Facilitated Diffusion 80
2.2.7 Enzymatic Reactions 84
2.3 Determination of Relaxation Constants 87
2.3.1 Stimulus-Response Relations 87
2.3.2 Regression Analysis 88
2.3.3 Deconvolution of Response Function by Differentiation 90
2.3.4 Deconvolution by Temporal Transformation 92
2.3.5 Deconvolution of Response Function by Linearization 103
2.4 Application of Relaxation Constants 108
2.4.1 Peroxidation 108
2.4.2 Dopaminergic Neurotransmission 108
3 Analysis of Neuroreceptor Binding In Vivo 119
3.1 The Receptor Concept 119
3.2 The Compartment Concept 121
3.2.1 Compartmental Analysis 121
3.2.2 The Basic Equation 122
3.2.3 The Basic Solution 123
3.3 Two-Compartment (Permeability) Analysis 124
3.3.1 Analysis of K1 and k2 124
3.3.2 Physiological Definitions of K1 and k2 126
3.4 Three-Compartment (Binding) Analysis 127
3.4.1 Analysis of k3 and k4 127
3.4.2 Molecular Definitions of k3 and k4 131
3.4.3 Inhibition 134
3.4.4 The Problem of Solubility and Nonspecific Binding 136
3.4.5 The Problem of Labeled Metabolites 138
3.5 In Vivo Analysis of Binding 138
3.5.1 Irreversible Binding: Determination of k3 138
3.5.2 Reversible Binding: Determination of BindingPotential (pB) 140
3.5.3 Equilibrium Analysis: Determination of Bmax and KD 142
4 Neuroreceptor Mapping In Vivo: Monoamines 146
4.1 Introduction 146
4.2 Monoaminergic Neurotransmission 146
4.3 Methods of Neuroreceptor Mapping 148
4.3.1 Tracers of Monoaminergic Neurotransmission 151
4.3.2 Pharmacokinetics of Monoaminergic Neurotransmission 155
4.4 Altered Monoaminergic Neurotransmission 160
4.4.1 Dopamine 161
4.4.2 Serotonin 164
4.4.3 Design of Monoaminergic Drugs 166
4.5 Conclusions 166
5 Blood--Brain Transfer and Metabolism of Oxygen 168
5.1 Introduction 168
5.2 Blood--Brain Transfer of Oxygen 169
5.2.1 Capillary Model of Oxygen Transfer 169
5.2.2 Compartment Model of Oxygen Transfer 172
5.3 Oxygen in Brain Tissue 174
5.3.1 Cytochrome Oxidation 174
5.3.2 Mitochondrial Oxygen Tension 176
5.4 Flow-Metabolism Coupling of Oxygen 180
5.5 Limits to Oxygen Supply 182
5.5.1 Distributed Model of Insufficient Oxygen Delivery 183
5.5.2 Compartment Model of Insufficient Oxygen Delivery 186
5.6 Experimental Results 187
5.6.1 Brain Tissue and Mitochondrial Oxygen Tensions 187
5.6.2 Flow-Metabolism Coupling 188
5.6.3 Ischemic Limits of Oxygen Diffusibility 191
6 Blood--Brain Glucose Transfer 192
6.1 Brief History 192
6.2 Brain Endothelial Glucose Transporter 193
6.2.1 Molecular Biology 193
6.2.2 Molecular Kinetics 195
6.2.3 Structural Requirements of Glucose Transport 196
6.3 Theory of Blood--Brain Glucose Transfer 197
6.3.1 Apparent Permeability and Flux 198
6.3.2 Facilitated Diffusion 201
6.3.3 Multiple Membranes 204
6.4 Evidence of Blood--Brain Glucose Transfer 206
6.4.1 Methods 207
6.4.2 Normal Values in Awake Subjects 211
6.4.3 Acute Changes of Glucose Transport 216
6.4.4 Chronic Changes 221
7 Metabolism of Glucose 226
7.1 Basic Principles of Metabolism 226
7.1.1 Glycolysis 227
7.1.2 Oxidative Phosphorylation 229
7.1.3 Gluconeogenesis 229
7.1.4 Glycogenesis and Glycogenolysis 230
7.1.5 Pentose-Phosphate Pathway 230
7.2 Kinetics of Steady-State Glucose Metabolism 230
7.3 Kinetics of Deoxyglucose Metabolism 232
7.3.1 Irreversible Metabolism 234
7.3.2 Lumped Constant 235
7.3.3 Reversible Metabolism 236
7.4 Operational Equations 239
7.4.1 Irreversible Metabolism of Deoxyglucose 239
7.4.2 Reversible Metabolism of Fluorodeoxyglucose 244
7.4.3 Metabolism of Tracer Glucose 246
7.5 Glucose Metabolic Rates 248
7.5.1 Lumped Constant Variability 250
7.5.2 Whole-Brain Glucose Consumption 252
7.5.3 Regional Brain Glucose Consumption 253
8 Neuroenergetics 255
8.1 Brain Work 255
8.2 Ion Homeostasis 256
8.3 Brain Energy Metabolism 258
8.3.1 Definition of Brain Activity Levels 258
8.3.2 Stages of Brain Metabolic Activity 260
8.4 Substrate Transport in Brain 262
8.4.1 Glucose Transport 262
8.4.2 Monocarboxylate Transport 263
8.4.3 Oxygen Transport 264
8.5 ATP Homeostasis 266
8.5.1 Hydrolysis of Phosphocreatine 267
8.5.2 Glycolysis 267
8.5.3 Oxidative Phosphorylation 270
8.6 Metabolic Compartmentation 273
8.6.1 Functional Properties of Neurons and Astrocytes 273
8.6.2 Metabolic Properties of Neurons and Astrocytes 274
8.7 Activation 279
8.7.1 Ion Homeostasis During Activation 280
8.7.2 Brain Energy Metabolism During Activation 281
8.7.3 Substrate Delivery During Activation 287
8.7.4 ATP Homeostasis During Activation 295
8.7.5 Metabolic Compartmentation During Activation 300
8.8 Conclusions 302
Glossary 305
References 315
Index 348