Neurokinetics

Summary

This book summarizes 20 years of work on the kinetics of blood-brain transfer and metabolism mechanisms in mammalian brain. The substances affiliated with these mechanisms include glucose, amino acids, monocarboxylic acids, and oxygen. These substances are important to energy metabolism and neurotransmission in the mammalian brain at rest and during activation. To understand the processes addressed by these mechanisms, the book examines the kinetics of compartmentation and compartmental analysis, particularly as they relate to transporter, enzyme, and receptor function. Compartments are subsets of substances separated by transporters and receptors in membranes, and enzymes in cells. This book is divided in six major chapters covering compartmental analysis, kinetic analysis of transport and metabolism, blood-brain transfer and metabolism of glucose, amino acids, and oxygen, and amino acid metabolism and interaction of amino acid metabolites with receptors.

Author Biography

Albert Gjedde is Professor and Chairman at the Department of Neuroscience and Pharmacology at the University of Copenhagen. He previously served as director of neuroimaging laboratories in Aarhus, Denmark, and Montreal, Canada. In Denmark, Albert Gjedde founded three brain research centers; the PET-center of Aarhus University Hospitals, the Center of Functionally Integrative Neuroscience of Aarhus University, and the Danish Neuroscience Center of Aarhus University. Dr. Gjedde holds adjunct professorships at McGill University, Aarhus University, and Johns Hopkins University. His research interest is the dynamics of neurotransmission and brain energy metabolism. William R. Bauer is a Mathematician and engineer. His expertise is in applied mathematics and related disciplines. He is a consultant to the Department of Radiology at Johns Hopkins University, specializing in algorithm development and techniques for estimating physiological parameters from PET data. Dean F. Wong is Professor of Radiology, Psychiatry, Neuroscience and Environmental Health Sciences, Vice-Chair of Radiology Administration and Training at Johns Hopkins University, and Director of the Section of High Resolution Brain PET (HRRT) Imaging within Nuclear Medicine/Radiology. His research involves the design, development, quantification, and application of radiopharmaceuticals imaged by positron emission tomography (PET) and single photon emission computed tomography (SPECT) for the study of in vivo brain chemistry dedicated to the study of neuropsychiatric disorders and their treatment using psychopharmacology.

Introduction to Compartmental Analysis	p. 1
Concept of Compartments	p. 1
Living Systems	p. 1
Thermodynamics and Entropy	p. 3
Fundamental Solution	p. 6
Limitations of Compartmental Analysis	p. 6
Single Tissue Compartment Analysis	p. 7
Two Tissue Compartment Analysis	p. 9
Compartmental Assumptions	p. 9
Combined Compartments	p. 12
Arteries and Veins	p. 13
Three Tissue Compartment Analysis	p. 14
Compartmental Assumptions	p. 15
Combined Compartments	p. 20
Fundamentals of Compartmental Kinetics	p. 23
Definition of Relaxation Constants	p. 23
Single Compartment	p. 24
Two Compartments	p. 25
Two Compartments with Sink	p. 28
Three Compartments	p. 30
Three Compartments with Sink	p. 34
Four or More Compartments	p. 36
Multiple Compartments in Series and in Parallel	p. 39
Interpretation of Relaxation Constants	p. 42
Flow	p. 42
Passive Diffusion	p. 43
Properties of Delivery Compartment	p. 49
Protein-Ligand Interaction	p. 56
Receptor Binding	p. 61
Facilitated Diffusion	p. 63
Enzymatic Reactions	p. 67
Determination of Relaxation Constants	p. 70
Stimulus-Response Relations	p. 70
Regression Analysis	p. 71
Deconvolution of Response Function by Differentiation	p. 73
Deconvolution by Temporal Transformation	p. 75
Deconvolution of Response Function by Linearization	p. 86
Application of Relaxation Constants	p. 91
Peroxidation	p. 91
Dopaminergic Neurotransmission	p. 91
Analysis of Neuroreceptor Binding In Vivo	p. 103
The Receptor Concept	p. 103
The Compartment Concept	p. 105
Compartmental Analysis	p. 105
The Basic Equation	p. 106
The Basic Solution	p. 107
Two-Compartment (Permeability) Analysis	p. 108
Analysis of K₁ and k₂	p. 108
Physiological Definitions of K₁ and k₂	p. 110
Three-Compartment (Binding) Analysis	p. 111
Analysis of k₃ and k₄	p. 111
Molecular Definitions of k₃ and k₄	p. 115
Inhibition	p. 118
The Problem of Solubility and Nonspecific Binding	p. 120
The Problem of Labeled Metabolites	p. 122
In Vivo Analysis of Binding	p. 122
Irreversible Binding: Determination of k₃	p. 122
Reversible Binding: Determination of Binding Potential (p_B)	p. 124
Equilibrium Analysis: Determination of B_max and K_D	p. 126
Neuroreceptor Mapping In Vivo: Monoamines	p. 131
Introduction	p. 131
Monoaminergic Neurotransmission	p. 131
Methods of Neuroreceptor Mapping	p. 133
Tracers of Monoaminergic Neurotransmission	p. 136
Pharmacokinetics of Monoaminergic Neurotransmission	p. 140
Altered Monoaminergic Neurotransmission	p. 145
Dopamine	p. 146
Serotonin	p. 149
Design of Monoaminergic Drugs	p. 151
Conclusions	p. 151
Blood-Brain Transfer and Metabolism of Oxygen	p. 153
Introduction	p. 153
Blood-Brain Transfer of Oxygen	p. 154
Capillary Model of Oxygen Transfer	p. 154
Compartment Model of Oxygen Transfer	p. 157
Oxygen in Brain Tissue	p. 159
Cytochrome Oxidation	p. 159
Mitochondrial Oxygen Tension	p. 161
Flow-Metabolism Coupling of Oxygen	p. 165
Limits to Oxygen Supply	p. 167
Distributed Model of Insufficient Oxygen Delivery	p. 168
Compartment Model of Insufficient Oxygen Delivery	p. 171
Experimental Results	p. 172
Brain Tissue and Mitochondrial Oxygen Tensions	p. 172
Flow-Metabolism Coupling	p. 173
Ischemic Limits of Oxygen Diffusibility	p. 176
Blood-Brain Glucose Transfer	p. 177
Brief History	p. 177
Brain Endothelial Glucose Transporter	p. 178
Molecular Biology	p. 178
Molecular Kinetics	p. 180
Structural Requirements of Glucose Transport	p. 181
Theory of Blood-Brain Glucose Transfer	p. 182
Apparent Permeability and Flux	p. 183
Facilitated Diffusion	p. 186
Multiple Membranes	p. 189
Evidence of Blood-Brain Glucose Transfer	p. 191
Methods	p. 192
Normal Values in Awake Subjects	p. 196
Acute Changes of Glucose Transport	p. 201
Chronic Changes	p. 206
Metabolism of Glucose	p. 211
Basic Principles of Metabolism	p. 211
Glycolysis	p. 212
Oxidative Phosphorylation	p. 214
Gluconeogenesis	p. 214
Glycogenesis and Glycogenolysis	p. 215
Pentose-Phosphate Pathway	p. 215
Kinetics of Steady-State Glucose Metabolism	p. 215
Kinetics of Deoxyglucose Metabolism	p. 217
Irreversible Metabolism	p. 219
Lumped Constant	p. 220
Reversible Metabolism	p. 221
Operational Equations	p. 224
Irreversible Metabolism of Deoxyglucose	p. 224
Reversible Metabolism of Fluorodeoxyglucose	p. 229
Metabolism of Tracer Glucose	p. 231
Glucose Metabolic Rates	p. 233
Lumped Constant Variability	p. 235
Whole-Brain Glucose Consumption	p. 237
Regional Brain Glucose Consumption	p. 238
Neuroenergetics	p. 241
Brain Work	p. 241
Ion Homeostasis	p. 242
Brain Energy Metabolism	p. 244
Definition of Brain Activity Levels	p. 244
Stages of Brain Metabolic Activity	p. 246
Substrate Transport in Brain	p. 248
Glucose Transport	p. 248
Monocarboxylate Transport	p. 249
Oxygen Transport	p. 250
ATP Homeostasis	p. 252
Hydrolysis of Phosphocreatine	p. 253
Glycolysis	p. 253
Oxidative Phosphorylation	p. 256
Metabolic Compartmentation	p. 259
Functional Properties of Neurons and Astrocytes	p. 259
Metabolic Properties of Neurons and Astrocytes	p. 260
Activation	p. 265
Ion Homeostasis During Activation	p. 266
Brain Energy Metabolism During Activation	p. 267
Substrate Delivery During Activation	p. 273
ATP Homeostasis During Activation	p. 281
Metabolic Compartmentation During Activation	p. 286
Conclusions	p. 288
Glossary	p. 291
References	p. 301
Index	p. 335
Table of Contents provided by Ingram. All Rights Reserved.

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