内容

目次

1 Transport and Storage of Catecholamines in Vesicles.- A. Introduction.- B. Biogenesis.- I. Formation and Types of Vesicles.- II. Biogenesis of Proteins, Mucopolysaccharides and Phospholipids.- III. Biogenesis of Catecholamines.- IV. Biogenesis of ATP.- C. Uptake.- I. Uptake of Catecholamines.- 1. Dependence on Temperature: Nucleotide and Ionic Requirements.- 2. Specificity of the Uptake of Catecholamines: Structure-Uptake Relationship.- 3. Stereospecificity of the Uptake of Catecholamines.- 4. Uptake of Catecholamines into Different Synaptic Vesicles of the Brain.- 5. Effects of Drugs on the Uptake of Catecholamines.- a. Inhibition by Drugs which Deplete Catecholamines.- b Inhibition by Monoamines.- 6. Ontogenesis of the Uptake of Catecholamines into Synaptic Vesicles.- II. Uptake of Nucleotides.- III. Uptake of Ascorbate.- IV. Enzymes Involved in the Uptake of Catecholamines, Nucleotides and Ascorbate.- 1. ATPase.- 2. Phosphoryl Group-Transferring Enzymes.- 3. Electron-Transferring Enzymes.- V. Uptake of Calcium.- VI. Utilization of Energy Required for Uptake.- 1. pH of Chromaffin Granules.- 2. Ion Movements Across the Chromaffin Granule Membrane.- a. Ion Permeability of the Membrane.- b. Generation of an Electrochemical Gradient Across the Membrane.- 3. Bioenergetic Aspects of the Uptake of Catecholamines and ATP.- D. Stroage.- I. Storage in Chromaffin Granules.- II. Storage in Synaptic Vesicles.- E. References.- 2 Occurrence and Mechanism of Exocytosis in Adrenal Medulla and Sympathetic Nerve.- A. Introduction.- B. Evidence for Exocytosis.- I. Adrenal Medulla.- 1. Biochemical Evidence for Exocytosis.- a. Secretion of Soluble Proteins from Chromaffin Granules.- b. Secretion of Other Soluble Constituents of Chromaffin Granules.- c. Retention of Membrane Constituents During Secretion..- d. Exposure of Membrane Antigens of Chromaffin Granules on Cell Surface During Secretion.- 2. Morphological Evidence for Exocytosis.- 3. Exocytosis: An All or None Release Process.- 4. The Fate of the Granule Membrane After Exocytosis.- 5. Conclusions.- II. Sympathetic Nerve.- 1. Biochemical Evidence for Exocytosis.- a. Secretion of Chromogranin A, Dopamin ß-Hydroxylase and Enkephalin.- b. Secretion of Other Constituents from Noradrenaline Storage Vesicles.- c. Conclusions.- 2. Morphological Evidence for Exocytosis.- 3. Immunohistochemical Evidence for Exocytosis.- 4. Electrophysiological Evidence for Exocytosis.- 5. The Contribution of Large and Small Dense Core Vesicles to Exocytosis and Their Possible Relationship.- 6. Conclusions.- C. Mechanism of Exocytosis.- I. Molecular Organization of Membranes Involved in Exocytosis.- II. Additional Factors Necessary for Exocytosis.- 1. Metabolic Energy.- 2. Calcium.- 3. Cyclic Nucleotides.- 4. Protein Kinase C, Polyphosphoinositide Metabolism and Contents GTP-Binding Proteins.- 5. Metalloendoprotease.- III. The Mechanism of Membrane Attachment.- 1. The Role of Contractile Proteins.- 2. The Role of Changes in the Charge of Granule Membranes.- a. Phosphorylation of Phosphatidylinositol.- b. Phosphorylation of Proteins of Granule Membranes.- c. Methylation of Granule Membrane Components.- 3. The Role of Calcium and Specific Proteins.- 4. Conclusions.- IV. Mechanism of Fusion.- 1. The Behaviour of Membrane Proteins During Fusion.- 2. The Role of Lipids in Fusion.- 3. Relationship of Fusion and Mg2+-ATP Release Reaction..- V. Experimental Models for Elucidating the Mechanism of Exocytosis in Adrenal Medulla.- VI. General Conclusions.- D. References.- 3 Monamine Oxidase.- A. Introduction.- B. Classification.- C. Distribution and Localization.- D. Properties of the Enzyme.- I. Molecular Weight.- II. Cofactors.- 1. Flavin.- 2. Metal Ions.- III. The Active Site.- E. Kinetics of the Reaction.- F. Reaction Mechanism.- G. Specificity.- H. The Influence of Membrane Environment.- J. Multiple Forms.- I. Electrophoretic Studies.- II. Selective Inhibitors.- III. Substrate Specificities.- IV. Other Evidence for Multiple Forms.- V. The Nature of the Two Forms.- VI. Evidence for an Association of Type A Activity with Neurones.- K. Multiple Forms as an In Vivo Reality and Their Function.- I. Evidence from Animal Studies.- II. Evidence from Human Studies.- L. Inhibitors.- I. Classification and Mechanism of Action.- 1. Hydrazines.- 2. Cyclopropylamines.- 3. Propargylamines.- 4. Reversible Inhibitors.- II. Selectivity of MAO Inhibition — Acute vs. Chronic Studies.- III. Pharmacological Actions of MAO Inhibitors.- 1. Interaction with Centrally-Acting Drugs.- 2. Potentiation of Peripheral Effects of Sympathomimetic Amines.- a. Effects of Inhibition of Extraneuronal MAO on the Actions of Indirect Sympathomimetic Amines.- b. Effects of Inhibition of Neuronal MAO on the Actions of Indirect Sympathomimetic Amines.- 3. Effects on Blood Pressure.- 4. Other Pharmacological Effects of MAO Inhibitors.- M. Physiological Role and Functional Activity of MAO; Biochemical and Behavioural Correlates.- N. Psychiatric and Neurological Disorders: MAO Activity and MAO Inhibitors as Drugs.- I. Depressive Illness.- II. Parkinson’s Disease.- O. Future Perspectives.- P. Addendum.- Q. References.- 4 The Transport of Amines Across the Axonal Membranes of Noradrenergic and Dopaminergic Neurones.- A. Introduction.- B. Neuronal Uptake.- I. Terminology and Methodology.- 1. Definition of Terms.- 2. Methodological Considerations.- II. Characteristics of Neuronal Uptake.- 1. Basic Properties.- 2. Structural Requirements.- 3. Temperature-Dependence and Metabolic Requirements.- 4. Ionic Requirements.- III. Inhibitors of Neuronal Uptake.- 1. Cocaine.- 2. Tricyclic Antidepressants and Related Compounds..- 3. Irreversible Uptake Inhibitors.- 4. Monovalent Cations.- 5. Binding Studies with Inhibitors of Neuronal Uptake.- C. Neuronal Amine Metabolism.- I. Formation of Metabolites Through MAO Activity.- II. Is There any Intraneuronal Formation of O-Methylated Metabolites?.- D. Neuronal Efflux.- I. Terminology and Methodology.- II. Spontaneous Neuronal Efflux.- III. Carrier-Mediated Neuronal Efflux.- 1. Efflux Induced by Phenylethylamines.- 2. Efflux Induced by Changes in Transmembrane Ion Gradients.- E. Proposed Mechanism of Neuronal Uptake: A Summing up.- I. General Considerations.- II. Models Accounting for the Ion-Dependence.- F. References.- 5 The Mechanism of Action of Indirectly Acting Sympathomimetic Amines.- A. Introduction.- B. The Adrenergic Nerve Ending.- I. Inward Transport by Uptake1.- II. The Outward Transport of Noradrenaline.- III. The Effect of Reserpine-like Drugs.- C. The Experimental Models.- I. Adrenergic Nerve Endings After Inhibition of Vesicular Uptake and of MAO.- II. Adrenergic Nerve Endings After Inhibition of MAO..- III. Intact Adrenergic Nerve Endings.- D. Carrier-Mediated Uptake of (+)-Amphetamine.- E. The Release of 3H-Noradrenaline After Inhibition of MAO and of Vesicular Uptake.- F. Factors Involved in the Release of Axoplasmic 3H-Noradrenaline.- I. Facilitated Exchange Diffusion.- H. The Co-transport of Sodium.- III. The Co-transport of Chloride.- IV. Inhibition of Neuronal Re-uptake.- G. The Release of 3H-Noradrenaline from Adrenergic Nerve Endings with Intact Storage Vesicles and Intact MAO (COMT Inhibited).- H. The Effects of Indirectly Acting Amines in the Presence of a Reserpine-like Compound.- J. Factors Which Influence the 3H-Noradrenaline-Releasing Effect of Indirectly Acting Amines.- I. Neuronal Uptake.- II Inhibition of Neuronal MAO.- III. The Existence of a Reserpine-like Effect for the Indirectly Acting Amine.- IV. Mobilization of Vesicular 3H-Noradrenaline.- V. Exocytotic Release in the Absence of Extracellular Calcium.- VI. The Axoplasmic Compartment(s).- K. The Release by Indirectly Acting Amines of Dopamine from Dopaminergic Nerve Endings.- L. Conclusions.- M. References.- 6 The Extraneuronal Uptake and Metabolism of Catecholamines.- A. Introduction.- I. The Extraneuronal System.- II. Other Non-neuronal Systems.- B. Uptake2.- I. Inward Transport.- 1. Definition and Occurrence of Uptake2.- 2. The Stereoselectivity of Uptake2.- 3. The Substrate Spectrum of Uptake2.- 4. The Distribution of 3H-Catecholamines in the Rat Heart.- 5. The “Lipophilic Entry” of Agents into Extraneuronal Cells.- II. Outward Transport.- 1. The Susceptibility of the Efflux of Catecholamines to Inhibition of Uptake2.- 2. The Interaction Between Different Substrates of Uptake2.- III. The Effects of Various Ions on Uptake2.- C. The Extraneuronal Metabolizing Systems.- I. The Extraneuronal O-Methylating System.- 1. The Kinetic Constants.- 2. The Revised Mathematical Model.- 3. The Functional Characteristics.- 4. The Intracellular Enzyme.- 5. The Increase of Sinside Induced by Inhibition of the Intracellular Enzyme.- 6. The Importance of “Lipophilic Entry” of Catecholamines.- II. The Extraneuronal Deaminating System.- III. The Co-existence of the Two Extraneuronal Enzymes.- D. Supersensitivity to Catecholamines After Inhibition of the Extraneuronal O-Methylating System.- E. The Interaction Between the Neuronal and the Extraneuronal Sites of Loss.- F. Conclusions: A Comparison of Uptake2 with Uptake1.- G. References.- 7 Catecholamines Receptors.- A. Introduction.- B. Relationship of Catecholamine Receptors to Effector Systems.- I. Cyclic AMP Formation.- II. Calcium Flux and Phosphatidylinositol Breakdown.- III. Other Effects of Catecholamines.- C. In Vitro Binding Assays.- I. Assay of ?-Adrenoceptors.- II. Assay of ?-Adrenoceptors.- III. Assay of Dopamine Receptors.- D. In Vitro Properties of Adrenoceptors.- I. Effects of Guanine Nucleotides.- 1. Effects of Guanine Nucleotides on ?-Adrenoceptors.- 2. Effects of Guanine Nucleotides on ?-Adrenoceptors.- 3. Effects of Guanine Nucleotides on Dopamine Receptors.- II. Effects of Ions.- 1. Effects of Ions on ?-Adrenoceptors.- 2. Effects of Ions on ?-Adrenoceptors.- 3. Effects of Ions on Dopamine Receptors.- III. Energetics of the Interactions of Agonists and Antagonists with Catecholamine Receptors.- 1. Energetics of Interactions with ?-Adrenoceptors.- 2. Energetics of Interactions with Dopamine Receptors.- IV. Effects of Membrane Altering Agents.- 1. Effects on ?-Adrenoceptors.- 2. Effects on Dopamine Receptors.- E. Localization of Catecholamine Receptors.- F. Multiplicity of Catecholamine Receptor Subtypes.- I. ?-Adrenoceptor Subtypes.- II. ?-Adrenoceptor Subtypes.- III. Dopamine Receptor Subtypes.- IV. Assay of Receptor Subtypes.- G. Regulation of the Sensitivity of Catecholamine Receptor Systems.- I. Effects of Decreased Stimulation.- II. Effects of Increased Stimulation.- III. Specific Alterations in Receptor Subtypes Caused by Changes in the Availability of Neurotransmitters.- IV. Regulation of Responsiveness Not Mediated by Changes in the Density of Receptors.- V. Effects of Hormones on Catecholamine Receptors and Responsiveness.- H. Agonist-Induced Desensitization.- J. Ontogeny of Catecholamine Receptors in the Central Nervous System.- K. Solubilization, Purification, and Reconstitution of Catecholamine Receptor/Effector Systems.- L. Molecular Cloning of Catecholamine Receptors.- M. Conclusion.- N. References.- 8 Presynaptic Receptors on Catecholamine Neurones.- A. Introduction and Definition of Terms.- B. The Dopamine Autoreceptor.- I. Basic Functions of the Dopamine Autoreceptor.- 1. Modulation of Depolarization-Evoked Dopamine Release.- a. The Origins of the Hypothesis that Dopamine Autoreceptors Modulate Dopamine Release.- b. Seven Years of Controversy.- c. The Dopamine Autoreceptor Modulating 3H-Dopamine Release Rediscovered.- d. A Physiological Role for the Dopamine Autoreceptor?.- e. The Mechanism of Action of the Dopamine Autoreceptor Modulating Depolarization-Evoked Release of 3H-Dopamine.- f. Are Autoreceptors Located on Dopaminergic Terminals or is There a Trans-synaptic Second Messenger?.- g. Autoreceptor Modulation of 3H-Dopamine Release from Synaptosomes.- h. Conclusions.- 2. Synthesis of Dopamine, In Vitro and In Vivo.- a. The Origins of the Hypothesis that Dopamine Autoreceptors Modulate the Synthesis of Dopamine.- b. The Localization of Synthesis-Modulating Dopamine Autoreceptors to Dopaminergic Terminals.- c. The Case Against Dopamine Autoreceptors Modulating the Synthesis of Dopamine.- d. Conclusions.- 3. Electrical Activity of Dopaminergic Neurones.- a. The Origins of the Hypothesis that Dopamine Autoreceptors Modulate the Firing of Dopaminergic Neurones.- b. The Debate over the Polysynaptic Feedback Loop vs. an Autoreceptor Mechanism for the Actions of Amphetamine.- c. Autoreceptor Mechanism for the Effects of Apomorphine and Dopamine on the Firing of Dopaminergic Neurones.- d. Pharmacological Aspects of the Dopamine Autoreceptor Modulating the Firing of Dopaminergic Neurones.- e. Electrophysiological Aspects of the Function of the Dopamine Autoreceptor.- f. Conclusions.- g. Questions for Future Electrophysiological Studies of Dopamine Autoreceptors.- II. Studies on the Functions of the Dopamine Autoreceptor.- 1. Locomotor Sedation.- a. The Origin of Behavioural Models for Dopamine Autoreceptor Function.- b. Criticisms of the Autoreceptor Hypothesis as the Mechanism of Locomotor Sedation Induced by Low Doses of Dopamine Receptor Agonists.- 2. “Turnover” of Dopamine.- a. Release of Newly Synthesized and Endogenous Dopamine.- b. Disappearance of Dopamine After a-Methyl-tyrosine Administration.- c. The ?-Butyrolactone Model.- d. Measurement of Dopamine Metabolites.- ?. The Involvement of Autoreceptors vs. the Long-Loop Feed-back.- ?. Effects of Chronic Administration of Neuroleptics on Dopamine Metabolite Levels.- III. Receptor Binding Identification of the Dopamine Autoreceptor.- 1. Successes and Failures in Detecting Dopamine Autoreceptors with Receptor Binding Techniques.- 2. The Proliferation of Dopamine Receptor Binding Sub-sites and Their Questionable Relationship to Functional Dopamine Receptors.- 3. D3:A Binding Site in Search of a Function.- 4. Conclusions.- IV. Dopamine Neurones Without Autoreceptors.- 1. The Frontal Cortex.- 2. The Median Eminence.- V. The Role of Somatodendritic Dopamine Autoreceptors...- VI. The Pharmacological Characteristics of the Dopamine Autoreceptor.- 1. In Vitro Pharmacological Characterization of Dopamine Autoreceptors.- 2. In Vivo Pharmacological Characterization of Dopamine Autoreceptors.- VII. Potential Clinical Relevance of Dopamine Autoreceptors..- 1. A Model for the Pre- and Postsynaptic Actions of Neuroleptics.- 2. The Therapeutic Mechanism of Action of Neuroleptics..- 3. A Role of the Dopamine Autoreceptor in the Therapeutic Action of Neuroleptics?.- 4. Agonists Acting at the Dopamine Autoreceptor: Potential as Therapeutic Agents.- C. Presynaptic Heteroreceptors Modulating Dopamine Function..- I. Cholinoceptors Modulating Dopamine Function.- II. Opiate Receptors Modulating Dopamine Function.- III. Excitatory Amino Acid Receptors Modulating Dopamine Function.- IV. GABA Receptors Modulating Dopamine Function.- V. Other Presynaptic Heteroreceptors Modulating Dopamine Function.- VI. The Physiological Relevance of Presynaptic Heteroreceptors..- D. Autoadrenoceptors.- I. Functions_of ?2 -Autoadrenoceptors.- 1. Modulation of Noradrenaline Release.- 2. Modulation of the Electrical Activity of Noradrenergic Neurones.- a. The Superior Cervical Ganglion.- b. The Locus Coeruleus.- II. Comparisons Between ?2-Autoadrenoceptors and the Dopamine Autoreceptor.- III. Presynaptic ?-Autoadrenoceptors on Peripheral Noradrenergic Neurones.- E. Presynaptic Dopamine Receptors Modulating Noradrenaline Release.- F. Conclusions.- G. References.- 9 Adaptive Supersensitivity.- A. Introduction.- B. The Induction of Adaptive Supersensitivity.- I. Experimental Procedures Which Have Been Used to Produce Supers ensitivity.- II. Effector Cell Activity (Use-Disuse) Versus Trophic Substances as Factors Regulating Sensitivity.- 1. Skeletal Muscle.- 2. Smooth Muscle.- C. Characteristics of Adaptive Supersensitivity.- I. Temporal Aspects.- II. Agonist Specificity.- D. Possible Mechanisms for Changes in Sensitivity of Effector Cells and Evidence Supporting or Opposing these Mechanisms.- I. Changes in Receptors.- 1. Skeletal Muscle and Application of Receptor Theory.- 2. Salivary Glands.- 3. Smooth Muscle.- 4. Cardiac Muscle.- 5. Pineal Gland.- 6. Peripheral and Central Nervous System.- II. Changes in Electrophysiolog