Handbook of

Neurochemistry SECOND EDITION

Volume 8 NEUROCHEMICAL SYSTEMS

Handbook of

Neurochemistry SECOND EDITION

Edited by Abel Lajtha Center for Neurochemistry, Wards Is/and, New York

Volume 1· CHEMICAL AND CELLULAR ARCHITECTURE

Volume 2· EXPERIMENTAL NEUROCHEMISTRY

Volume 3· METABOLISM IN THE NERVOUS SYSTEM

Volume 4· ENZYMES IN THE NER VOUS SYSTEM

Volume 5· METABOLIC TURNOVER IN THE NERVOUS SYSTEM

Volume 6· RECEPTORS IN THE NER VOUS SYSTEM

Volume 7· STRUCTURAL ELEMENTS OF THE NERVOUS SYSTEM

Volume 8· NEUROCHEMICAL SYSTEMS

Volume 9· ALTERA TIONS OF METABOLITES IN THE NER VOUS SYSTEM

Volume 10· PATHOLOGICAL NEUROCHEMISTRY

Handbook of

Neurochemistry SECOND EDITION

Volume 8 NEUROCHEMICAL SYSTEMS

Edited by

Abel Lajtha Center for Neurochemistry Wards Island. New York

PLENUM PRESS • NEW YORK AND LONDON

Library of Congress Cataloging in Publication Data

Main entry under title:

Handbook of neurochemistry.

Includes bibliographical references and indexes. Contents: v. 1. Chemical and cellular architecture-v. 2. Experimental neurochem­

istry-[etc.]-v. 8. Neurochemical systems-[etc.] 1. Neurochemistry - Handbooks, manuals, etc. - Collected works. 2. Neurochem­

istry. I. Lajtha, Abel. [DNLM: 1. Neurochemistry. WL 104 H434] QP356.3.H36 1982 612'.814 82-493

ISBN 978-1-4684-7020-8 ISBN 978-1-4684-7018-5 (eBook) DOl 10.1007/978-1-4684-7018-5

© 1985 Plenum Press, New York Softcover reprint of the hardcover 2nd edition 1985 A Division of Plenum Publishing Corporation 233 Spring Street, New York, N.Y. 10013

All rights reserved

No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

Contributors

Bernard W. AgranofJ, Neuroscience Laboratory Building and Mental Health Research Institute, University of Michigan, Ann Arbor, Michigan 48109

S. Arch, Biological Laboratories, Reed College, Portland, Oregon 97202

Nicolas G. Bazan, Lions Eye Research Laboratories, LSU Eye Center, Louisiana State University Medical Center School of Medicine, New Orleans, Louisiana 70112

M. Billingsley, Section on Biochemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland 20205

Laszlo Z. Bito, College of Physicians and Surgeons, Columbia University, New York, New York 10032

Carla Perrone Capano, Institute of General Physiology, Faculty of Sciences, University of Naples, and International Institute of Genetics and Biophysics, Naples, Italy

Priscilla S. Dannies, Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510

Philippa M. Edwards, Division of Molecular Neurobiology, Institute of Mo­"lecular Biology, Laboratory of Physiological Chemistry and Rudolf Magnus Institute for Pharmacology, State University of Utrecht, 3508 TB Utrecht, The Netherlands

H. Gainer, Laboratory of Developmental Neurobiology, National Institutes of Health, Bethesda, Maryland 20205

Candace J. Gibson, Department of Pathology, University of Western Ontario, London, Ontario N6A 5CI, Canada

v

vi Contributors

Willem Hendrik Gispen, Division of Molecular Neurobiology, Rudolf Magnus Institute for Pharmacology, and Institute of Molecular Biology, State U ni­versity of Utrecht, 3584 CH Utrecht, The Netherlands

Antonio Giuditta, Institute of General Physiology, Faculty of Sciences, U ni­versity of Naples, and International Institute of Genetics and Biophysics, Naples, Italy

Laszlo Graf, The Institute for Drug Research, 1325 Budapest, Hungary

Roger Guillemin, Laboratories for Neuroendocrinology, The Salk Institute, La Jolla, California 92037

I. Hanbauer, Section on Biochemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20205

L. Hertz, Department of Pharmacology, University of Saskatchewan, Saska­toon, Saskatchewan S7N OWO, Canada

Fran{:ois B. Jolicoeur, Department of Psychiatry, Faculty of Medicine, Uni­versity of Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada

B.H.J. Juurlink, Department of Anatomy, University of Saskatchewan, Sas­katoon, Saskatchewan S7N OWO, Canada

E. Ronald de Kloet, Rudolf Magnus Institute for Pharmacology, Medical Fac­ulty, University of Utrecht, 3521 GD Utrecht, The Netherlands

D. Kuhn, Section on Biochemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20205

Allen S. Levine, Neuroendocrine Research Laboratory, Minneapolis Veterans Administration Medical Center, Minneapolis, Minnesota 55417; and De­partments of Medicine and Food Science and Nutrition, University of Min­nesota, Minneapolis-St. Paul, Minnesota 55455

Bruce S. McEwen, The Rockefeller University, New York, New York 10021

Henry McIlwain, Department of Biochemistry, St. Thomas's Hospital Medical School, London SEI 7EH, England

John E . Morley, Neuroendocrine Research Laboratory, Minneapolis Veterans Administration Medical Center, Minneapolis, Minnesota 55417; and De­partments of Medicine and Food Science and Nutrition, University of Min­nesota, Minneapolis-St. Paul, Minnesota 55455

Contributors vii

Jacques Nunez, Unite de Recherche 35 de l'INSERM, and Equipe de Re­cherche sur la Biochimie de la Regulation Hormonale, CNRS, Hospital H. Mondor, 94 Creteil, France

Chandan Prasad, Departments of Medicine (Section of Endocrinology) and Biochemistry, Louisiana State University Medical Center, New Orleans, Louisiana 70112

Thomas C. Rainbow, Department of Pharmacology, University of Pennsyl­vania, Philadelphia, Pennsylvania 19104

T. Sanjeeva Reddy, Lions Eye Research Laboratories, LSU Eye Center, Louisiana State University Medical Center School of Medicine, New Or­leans, Louisiana 70112

Francis Rioux, Department of Physiology and Pharmacology, Faculty of Med­icine, University of Sherbrooke, Sherbrooke, Quebec JIH 5N4, Canada

Serge St.-Pierre, Department of Physiology and Pharmacology, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec JIH 5N4, Canada

Peter Schotman, Division of Molecular Neurobiology, Institute of Molecular Biology, Laboratory of Physiological Chemistry and Rudolf Magnus Institute for Pharmacology, State University of Utrecht, 3508 TB Utrecht, The Neth­erlands

Loes H. Schrama, Division of Molecular Neurobiology, Institute of Molecular Biology, Laboratory of Physiological Chemistry and Rudolf Magnus Institute for Pharmacology, State University of Utrecht, 3508 TB Utrecht, The Neth­erlands

Hitoshi Shichi, Institute of Biological Sciences, Oakland University, Roch­ester, Michigan 48063

S. Szuchet, Department of Neurology, University of Chicago, Chicago, Illinois 60637

Gyula Telegdy, Institute of Pathophysiology, University Medical School, Szeged, Hungary

Yasuzo Tsukada, Department of Physiology, Keio University School of Med­icine, Tokyo, Japan

H. Dick Veldhuis, Rudolf Magnus Institute for Pharmacology, Medical Faculty, University of Utrecht, 3521 GD Utrecht, The Netherlands

viii Contributors

Tony L. Yaksh, Department of Neurosurgical Research, Mayo Clinic, Roch­ester, Minnesota 55905

Gigliola Grassi Zucconi, Institute of Cell Biology, Faculty of Sciences, Uni­versity of Perugia, Perugia, Italy

Henk Zwiers, Division of Molecular Neurobiology, Rudolf Magnus Institute for Pharmacology, and Institute of Molecular Biology, State University of Utrecht, 3584 CH Utrecht, The Netherlands

Preface

The content of Volume 8 of the Handbook of Neurochemistry is a perfect example and sample of what occupies neurochemists in the late 1980s. What occupies them are questions, concepts, and technology that either did not start with the nervous system, or rapidly moved out of its exclusivity (see, for in­stance, chapters on neurotensin, beta-lipotropin, behavioral and neurochemical effects of ACTH, cholecystokinin, etc.). Thus, the neurochemist is more and more seen as a biochemist occupied by questions, concepts, and technology that are not unique to the nervous system, even though the ultimate substrate of these questions, as well as the ultimate functions so studied and occasionally explained, are of the nervous system.

Look at the case of the hypothalamic hypophysiotropic peptides, also called hypothalamic releasing factors, or hypothalamic releasing hormones. These are all small-to-medium-size polypeptides originally characterized in ex­tracts of the hypothalamus on the basis of bioassays directed at studying their effects on one or another of the secretions of the adenohypophysis. We know now that TRFs (See Chapter 8), the thyrotropin and prolactin releasing factor, somatostatin, the hypothalamic inhibitor of the secretion of growth hormone, as well as LRF, the hypothalamic decapeptide stimulating the secretion of pituitary gonadotropins, are to be found in parts of the brain other than the hypothalamus, where their function is obviously not hypophysiotropic. Such is also the case for CRF-the corticotropin and beta-endorphin releasing factor. Our original statement about the uniqUely hypothalamic location of the growth hormone releasing factor-GRF, somatocrinin, has recently been challenged by colleagues using polyclonal antisera different from those used by us, and they may well be right.

Furthermore, we know that these peptides, first of the hypothalamus, then of the brain, are also found in the spinal cord, peripheral nerves, and in various tissues of the gastrointestinal tract including the pancreas, and, in some forms with relatively minor structural variation, the skin of amphibians and even in various anatomical structures of invertebrates.

Similarly, all the biologically active peptides originally characterized in the gastrointestinal tract, the lungs, the kidney, and the teguments (of am­phibians) have been recognized as such or with minor structural variations in the brain, the spinal cord, and the peripheral nervous system of mammalians.

ix

x Preface

There is excellent evidence that in all locations we are dealing with the same polypeptide sequence or molecule.

In one location, these peptides will be called hormones, and will be called neuromediators or neuromodulators in other locations. I have already alluded to the fact that the hypothalamic hypophysiotropic peptides are also called hypothalamic hormones. We obviously have a problem of terminology. Should we ignore it?

The word hormone was originally introduced into the literature by Ernest Henry Starling on June 20, 1905, in the first of his Croonian Lectures delivered before the Royal College of Physicians in London on "The Chemical Corre­lation of the Functions of the Body". Starling frames the thinking within which the definition of hormones will appear: "The chemical adaptation or adapta­tions of the body, like those which are carried out through the intermediation of the central nervous system, can be divided into two main classes: 1) those which are involved in consequence of changes impressed upon the organism as a whole from without; and 2) those which, acting entirely within the body, serve to correlate the activities, in the widest sense of the term, of the different parts and organs of the bod y. " Then, after some discussion of the first category, he moves on to the second and says the following: "These chemical messen­gers, however, or hormones (from ormao, I excite, or arouse) as we might call them, have to be carried from the organ where they are produced to the organ which they affect, by means of the bloodstream, and the continually recurring physiological needs of the organism must determine their repeated production and circulation through the body".

Most of the substances which we call hormones to this day do meet these criteria; this is the case for the secretory products of all the endocrine glands. These circulate far and wide from their organ of production to the receptors of their target organs, where they somehow excite, stimulate, or cause some positive effect in the cells of that tissue. Physiologically meaningful levels of these hormones can now be measured by all sorts of exquisitely sensitive meth­ods in the peripheral blood with the added feature that there is always a de­monstrable arteriaUvenous difference in the concentration of these substances when measured in the inflow or outflow blood to and from the organ known to be the source of the hormone in question.

In the case ofthe hypothalamic peptides involved in the control of pituitary functions, there is reliable evidence that they can be demonstrated by bioassay or radioimmunoassay in the effluent blood from the hypothalamus when tapped in the portal vessels along the pituitary stalk. There is also no doubt that there is a difference in the concentrations found in the hypothalamic portal blood when compared to peripheral blood. This, however, is where the problems begin in calling these substances hormones. Reliable methodology shows that the peripheral levels of circulating thyrotropin releasing factor (TRF) or go­nadotropin releasing factor (LRF) are so low as to be of no physiological sig­nificance. In the case of somatostatin, the matter is even more complex. First, somatostatin is universally an inhibitor (of one secretion or another), and thus can hardly be called a "hormone", a name that etymologically implies "stim­ulation, excitation". But perhaps more important, it is now well recognized

Preface xi

that somatostatin has a ubiquitous distribution (though not random) ranging from the central nervous system to multiple locations of the gastrointestinal tract and the pancreas as we discussed above. Immunoreactive and bioactive somatostatin, in fact forms of somatostatin of various molecular sizes, can be demonstrated to circulate in peripheral blood (jugular vein in laboratory ani­mals, antecubital vein in man), but in concentrations that appear to be far below what can be calculated to be its binding or affinity constants. There is, however, excellent evidence that much larger concentrations of immunoreactive and bioactive somatostatin can be shown in more localized circulation such as in the effluent vein of the pancreas, where we know that somatostatin is present in the delta cells. There is also good evidence that these local plasma concen­trations of local somatostatin can vary considerably as a function of physio­logical or experimental situations (absorption of meals, injection of various peptides, such as cholecystokinin, or endorphins, or drugs such as opiates, or arginine). If TRF, LRF, and somatostatin are to be called hormones and con­sidered as such, then it must be said that they do not qualify as the classical hormones.

But things are even more complex. We know now that immunoreactive, as well as bioactive, TRF, LRF, somatostatin, the "gut hormones" cholecys­tokinin (see Chapter 5), VIP (vasoactive intestinal peptide), gastrin, etc., are found within discrete neurons, either in the cell body or in peripheral endings from which they certainly have to be released for physiological purposes which are not well understood at the moment. In such circumstances and setups, neither TRF, LRF, nor somatostatin or any of the other "gut hormones" be­haves as, or meets the criteria of, hormones. They seem to be involved in localized controls. It is probably also the case when trying to understand how pancreatic somatostatin could modify the secretion of insulin and glucagon by the nearby cells of the islets.

Because of their neuronal locations, TRF, LRF, somatostatin (and perhaps the other biologically active peptides such as neurotensin, endorphins, enke­phalins, VIP, etc.) have been proposed as neurotransmitters, as are catechol­amines or acetylcholine. But somatostatin is not a neurotransmitter when re­leased by the delta cells of the endocrine pancreas to affect the glucagon secretion by a nearby alpha cell, reaching either through gap junctions or ex­tracellular space. Noradrenalin in and out of neurons is the neurotransmitter, while adrenalin is the hormonal form in and from the adrenal medulla, with the small amounts of noradrenalin found in the adrenal medulla leaving us in a quandary.

It is thus obvious that the current terminology is wanting. Either we have to redefine what it is that we mean by hormone or some additional terminology has to be proposed.

The question is what to do with these ubiquitous molecules which have local effects that can range from angstroms to microns (gap junctions, extra­cellular spaces) in and from cells which include neurons, to centimeters, when dealing with local either splanchnic or pituitary locations. Such substances do not fit in well with the definition of a hormone or of a neurotransmitter. We have the word paracrine, as originally proposed by Feyrter to describe pre-

xii Preface

cisely the suspected secretory activities of what we now know to be the peptide­secreting cells of the gut. The etymology of the word is obvious and implies a local or nearby use or function for what is being secreted. I personally think that the word paracrine is excellent and should be used often in relation to the problem we are discussing here. But paracrine is an adjective, and to my knowl­edge Feyrter, in his difficult German, used it exclusively as such, referring to paracrine secretory cells and paracrine secretion. We could perhaps coin the word "parahormone" or "parhormone", but neither is euphonic or easy to pronounce in either French or English, or German for that matter. Several years ago I proposed the word cybernin, from the Greek "kurbenetes", mean­ing "pilot" or "rudder" of a boat, implying the local nature of the command or information involved. This is also the root of the well-known word cyber­netics, even though I could never ascertain whether Norbert Wiener implied any localization (of information) when he decided to use the word (according to Littre, the word "cybernetique" was coined by Ampere to define "la partie politique qui s'occupe des moyens de gouverner"). I never pushed very hard for the implantation of the word cybernin, feeling that it was another word, another root, without a clearly defined mission. The word. however, is being used by more and more people, thus appearing to fulfill a role. So, how should we use it? First of all, what is a cybernin? A cybernin is a polypeptide bio­synthesized, processed, and released by a cell or group of cells, that represents information that will affect the function of another cell or group of cells in the vicinity of the first cell or group of cells. Such a simple definition excludes all steroids, prostaglandins, or molecules such as cyclic-AMP. Would beta-endor­phin, ACTH, which certainly are hormones when secreted by the pituitary, be considered as cybernins when relating to their presence in hypothalamic neu­rons and when released either at nerve endings from these neurons (a statement which is only a proposal at the moment, albeit a logical one) or when released in the portal vessels of the pituitary of the median eminence and as measured in the down-flow blood along the pituitary stalk? The answer is yes. I would say that, in these circumstances, beta-endorphin and ACTH are seen, act, and should be considered, as cybernins. When we describe their action it will be referred to as a cybernin action rather than a hormonal action. Somatostatin will act as a cybernin when it modifies the secretion of insulin and glucagon in nearby pancreatic cells and originates from pancreatic delta cells; it will also be acting as a cybernin when proceeding to the adenohypophysis, inhibiting the secretion of growth hormone, when originating from the hypothalamus. I would prefer to consider somatostatin as a cybernin rather than as a neuro­transmitter if it can be shown that it is actually released at some axonal or dendritic ending and that it modifies the response of another neuron to anyone of the classical neurotransmitters. In fact, the word cybernin may turn out to be the optimal noun for the adjective paracrine. The polypeptidic growth factors recently proposed by Sporn and Todaro as "autocrine" secretions in the ul­timate of paracrine function could also be considered as cybernins.

The success of any nomenclature is based on need. The need for the use of the word cybernin is probably not compelling. However, since the words hormone, neuromediator, mediator, modulator, are either too restrictive or too

Preface xiii

vague in their definition or implied use, maybe there will be some feeling of comfort in the use of the word cybernin.

I have discussed above the ubiquity of these biologically active peptides. There is also evidence, though not so widely established, that the "receptor" molecules for these peptides in their ubiquitous locations are identical or share extensive common binding properties for related ligands. Thus what is specific (for the nervous system) if are neither the ligands, nor the receptors? There is evidence that not even the post- receptor-binding type of response is. What may be specific is the final result of the activation of a highly specialized neuron. What is specific finally is the functional response as seen in a system of neurons. And while (neuro)chemistry is necessary to understand the function of each cellular unit of that system, (neuro)chemistry does not tell us what will be the function of that system or how that function will take place. This is where the power, the immense power of reductionism as we know it currently comes to a halt, a pause, possibly a standstill-an "impossibility to proceed owing to exhaustion", says the Oxford dictionary. Rather than accepting this latest meaning of the word I'd rather use it as implying standing still, as in wait of some new paradigm, a true revolution in science, according to the terminology of Thomas Kuhne. How else could we engage in the neurochemical study of sleep while at the same time attempting to characterize sleep peptides?

Perhaps one of those new ways will be found in the emerging studies of what I will simply call nonlinear dynamics to refer to the mode of thinking or the concept that complexity when it reaches such a height that it is seen as chaos or apparent randomness can still generate its own periodic order. Phys­icists, chemists, and mathematicians like Haken, Prigogine, and Thom have all proposed mathematics to support this vastly novel way of thinking for the biologist and have already shown the powerful predictive value of such math­ematics in "explaining" the emergence of complex biological structures in embryogenesis, complex periodic functions in multicompartmental biological systems, etc. Psychiatrists like Mandell have already proposed that such think­ing could lead to new approaches to understand normal and abnormal patterns of behaviour, in some ways defining normal brain functions and behaviour from the absence of the characteristics of mental disorders.

And this is where so much of the subject matter of this volume comes back in focus: Many of the molecules discussed here have already been shown to affect the amplitude or frequency of one or another of these nonlinear dy­namics events as observed in the central nervous system. Perhaps here will be found a new generation of still reductionist questions, unless some genial holist takes us away from modern obscurantism in its glorious achievements.

Roger Guillemin

Contents

Chapter 1

Thyroid Hormones Jacques Nunez

1. Introduction .. . . . . . . . . . . . . . . . . . . . . . . . ................ . 2. Thyroid Function and the Development of Neuroendocrine

Control .......................................... 2 2.1. Thyroid Hormone Synthesis .......................... 3 2.2. Thyroid Hormone Secretion .......................... 4 2.3. Hormonal Control of Thyroid Function .................. 5 2.4. Ontogenesis of the Hypothalamic-Pituitary-Thyroid Axis .... 6

3. Thyroid Hormone Effects on Cell Acquisition and Neuronal Differentiation ........................................ 8 3.1. Cell Division and Cell Acquisition . . . . . . . . . . . . . . . . . . . . . . 9 3.2. Cell Migration and the Development of the Neuropil ........ 10 3.3. Synaptogenesis and Development of Nerve Cell

Transmitters ...................................... 12 3.4. Myelination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 12

4. Uptake, Metabolism, and Mechanism of Action of Thyroid Hormones ........................................... 14 4.1. Transport and Uptake of Thyroid Hormones by the CNS . . . . . 15 4.2. The Concept of "Active Form" and he Peripheral Conversion

of Thyroxine to Triiodothyronine. . . . . . . . . . . . . . . . . . . . . .. 16 4.3. Thyroid Hormone Binding Proteins and Receptors. . . . . . . . . . 17 4.4. Thyroid Hormones and Protein Synthesis ................ 19 4.5. The Role of the Cytoskeleton during Brain Differentiation .... 19

5. Neonatal Thyroid Screening and Replacement Therapy. . . . . . . . .. 22 6. Conclusions .......................................... 22

References ........................................... 23

Chapter 2

Mechanisms of Gonadal Steroid Actions on Behavior Thomas C. Rainbow and Bruce S. McEwen

1. Introduction .......................................... 29

xv

xvi Contents

2. Activational Effects of Gonadal Steroids on Behavior . . . . . . . . . .. 30 2.1. Genomic Mechanisms of Steroid-Activated Behaviors ....... 32 2.2. Target Cells for the Activation of Feminine Sexual

Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 34 2.3. Identification of Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 35

3. Organizational Actions of Gonadal Steroids on Behavior. . . . . . . .. 40 4. Organizational and Activational Effects of Gonadal Steroids and Their

Relevance for the Study of Memory Formation . . . . . . . . . . . . . . .. 43 References ..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 44

Chapter 3

Adrenocortical Hormone Action E. Ronald de Kloet and H. Dick Veldhuis

1. Introduction ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 47 2. Function of Adrenocortical Hormones ...................... 48 3. Steroid-Cell Interaction ................................. 49

3.1. Cellular Uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 49 3.2. Intracellular Biotransformation of Steroids. . . . . . . . . . . . . . .. 51 3.3. Activation of the Receptor and Transformation to Its DNA-Bind-

ing State .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 5 I 3.4. Translocation of the Steroid-Receptor Complex and Initiation of

Genomic Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 52 3.5. Steroid-Nerve Cell Interaction ........................ 53

4. Adrenal Steroid Receptors in Brain. . . . . . . . . . . . . . . . . . . . . . . .. 54 4.1. Cellular Localization of Corticosterone .................. 54 4.2. Cellular Localization of Mineralocorticoids and

Dexamethasone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 54 4.3. Competition for Cell Nuclear Localization of

Corticosterone .................................... 58 4.4. Cell Nuclear Uptake in Vitro in Tissue Slices ............. 58 4.5. Binding of Adrenal Steroids to Soluble Receptors .......... 59 4.6. Heterogeneity in Adrenal Steroid Receptor Systems ........ 60 4.7. Fractionation of Adrenal Steroid Receptor Sites ........... 62 4.8. Corticoid Receptors and CBG-like Proteins ............... 63

5. Regulation of the Adrenal Steroid Receptor System ............ 64 5.1. Neurotropic Substances. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 64 5.2. Compensatory Changes in Number of Steroid Receptor

Sites ............................................ 66 5.3. Ontogeny and Aging ................................ 67

6. Effects of Adrenal Steroids on Brain Chemistry ............... 68 6.1. Neurotransmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 69 6.2. Neuropeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 73 6.3. Proteins ......................................... 73 6.4. Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 74

Contents xvii

6.5. Morphology ...................................... 74 6.6. Other Actions ..................................... 75

7. Control of Brain Function by Adrenal Steroids ................ 75 7.1. Neuroendocrinology ................................ 76 7.2. Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 78

8. Concluding Remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 81 References ........................................... 82

Chapter 4

Neurotensin Franrois B. Jolicoeur, Francis Rioux, and Serge St.-Pierre

1. Introduction .......................................... 93 2. Distribution of Neurotensin in the Central Nervous System. . . . . .. 93 3. Metabolism of Neurotensin in the Central Nervous System. . . . . .. 95 4. Electrophysiological Studies .............................. 96 5. Neurobehavioral Effects of Central Administration of

Neurotensin .......................................... 96 5.1. Body Temperature ................................. 97 5.2. Muscular Tone .................................... 98 5.3. Motor Activity .................................... 98 5.4. Reactivity to Noxious Stimuli ......................... 99 5.5. Other Central Effects ............................... 101

6. Structure-Activity Studies ............................... 102 7. Interactions of Neurotensin with Dopamine and Other Neurotrans-

mitters .............................................. 104 7.1. Dopamine ........................................ 105 7.2. Neuroleptic Properties of Neurotensin . . . . . . . . . . . . . . . . . .. 106 7.3. Interactions with Other Neurotransmitters . . . . . . . . . . . . . . .. 108

8. Summary ............................................ 109 References ........................................... 110

Chapter 5

Cholecystokinin John E. Morley and Allen S. Levine

1. Introduction ......................................... 115 2. Central Nervous System Distribution ...................... 116 3. Cholecystokinin-Converting Enzymes ...................... 118 4. Cholecystokinin Receptors in the Brain. . . . . . . . . . . . . . . . . . . .. 119 5. Direct Effect of Cholecystokinin on Neurons. . . . . . . . . . . . . . . .. 120 6. Neuropharmacology of Cholecystokinin .................... 120

6.1. Hyperglycemia ................................... 121 6.2. Hypothermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 121

xviii Contents

6.3. Analgesia ....................................... 121 6.4. Rotational Syndrome .. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 122 6.5. Central Nervous System Depression and Exploratory

Behaviors ....................................... 122 7. Effects of Cholecystokinin on Pituitary Hormone Release ....... 123 8. Cholecystokinin and Satiety ............................. 124 9. Monoamines and Cholecystokinin ......................... 127

10. Conclusion .......................................... 129 References .......................................... 130

Chapter 6

~-Lipotropin

Laszlo Graf

1. Introduction ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 137 2. Structure ............................................ 138

2.1. Amino Acid Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 138 2.2. Conformation ..................................... 142

3. Biological Properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 142 4. Biosynthesis in the Pituitary . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 145

4.1. Pulse-Chase Studies: The Pathway of the Biosynthesis ...... 145 4.2. Nucleotide Sequencing of Cloned cDNA for the Precursor and

Protein Sequencing of the Biosynthetic Intermediates ....... 147 4.3. Proteinases Involved in the Processing of the Precursor and in

the Release of the Final Products ...................... 150 5. Occurrence in the Pituitary, Periphery, and Brain .. . . . . . . . . . . .. 151 6. Physiological Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 153

References ........................................... 154

Chapter 7

Prolactin Priscilla S. Dannies

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 159 2. Synthesis and Processing of Prolactin ....................... 159 3. Regulation of Prolactin Production ......................... 161

3.1. Agents That Regulate Prolactin Production by Acting Directly at the Pituitary Gland ................................. 161

3.2. Regulation at Levels Other Than the Pituitary Gland ........ 165 4. Physiological Patterns of Prolactin Secretion . . . . . . . . . . . . . . . . .. 165

4.1. Prolactin Secretion in Man ........................... 165 4.2. Prolactin Secretion in Rats ........................... 166 4.3. Factors That Regulate Physiological Changes in Prolactin Secre-

tion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 167

Contents xix

5. Intracellular Mechanisms by Which Prolactin Production Is Controlled ........................................... 168 5.1. Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 168 5.2. Synthesis ........................................ 169

6. Effects of Prolactin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 169 6.1. Prolactin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 170 6.2. Effects of Prolactin ................................. 171

7. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 172 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 172

References .............. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 172

Chapter 8

Thyrotropin-Releasing Hormone Chandan Prasad

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 175 2. Distribution and Modulation of Endogenous TRH

Concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 175 2.1. In Central Nervous System .... . . . . . . . . . . . . . . . . . . . . . .. 175 2.2. In Gastrointestinal Tract and Pancreas . . . . . . . . . . . . . . . . . .. 177 2.3. In Body Fluids and Other Tissues ...................... 178

3. Metabolism of TRH .................................... 179 3.1. Biochemical Pathways. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 179 3.2. Properties of the Enzymes. . . . . . . . . . . . . . . . . . . . . . . . . . .. 181 3.3. Regulation of TRH Metabolism. . . . . . . . . . . . . . . . . . . . . . .. 182 3.4. Possible Physiological Significance of TRH Metabolism. . . . .. 182

4. MUltiple Biological Effects of TRH . . . . . . . . . . . . . . . . . . . . . . . .. 184 4.1. Behavioral Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 184 4.2. Endocrine Effects .................................. 185 4.3. Cardiovascular Effects .............................. 187 4.4. Gastrointestinal Effects .............................. 187 4.5. Respiratory and Other Effects ......................... 188

5. Thyrotropin-Releasing Hormone as a Possible Neurotransmitter or Neuromodulator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 188 5.1. Uneven Distribution in Mammalian Brain and Spinal Corg . . .. 188 5.2. Synaptosomal Localization ........................... 190 5.3. Uptake and Release ................................ 190 5.4. The TRH Receptor ................................. 191 5.5. Action of TRH on Neurons . . . . . . . . . . . . . . . . . . . . . . . . . .. 192 5.6. Effect on Putative Neurotransmitter Metabolism ........... 193

6. Discussion ........................................... 193 References ........................................... 194

xx Contents

Chapter 9

Role of Calmodulin in the Regulation of Neuronal Function M. Billingsley, I. Hanbauer, and D. Kuhn

1. Introduction ........... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 201 2. Neurotransmitter Synthetic Enzymes ....................... 201

2.1. Tryptophan Hydroxylase . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 202 2.2. Tyrosine Hydroxylase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 205

3. Calcium- and Calmodulin-Stimulated Phosphorylation of Membrane Proteins in Nervous Tissue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 206 3.1~· Presynaptic Protein Phosphorylation .................... 207 3.2. Calmodulin-Stimulated Phosphorylation in Postsynaptic Densi-

ties .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 208 3.3. Phosphorylation of Myelin. . . . . . . . . . . . . . . . . . . . . . . . . . .. 209 3.4. Drug Effects on Ca2 + 'CaM-Dependent Phosphorylation of Mem­

brane Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 209 4. Postsynaptic Receptor Regulation . . . . . . . . . . . . . . . . . . . . . . . . .. 210

4.1. Regulatory Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 210 4.2. Desensitized and Supersensitive Dopamine Receptors ....... 211 References ........................................... 213

Chapter 10

Effects of Gastrointestinal Pep tides on the Nervous System Gyula Telegdy

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 217 2. Secretin ............................................. 218

2.1. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 220 2.2. Effect on Brain Function. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 220 2.3. Effect on Endocrine System .......................... 220 2.4. Conclusion ....................................... 220

3. Vasoactive Intestinal Polypeptide .......................... 220 3.1. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 221 3.2. Peripheral Action .................................. 221 3.3. Central Effects .................................... 222 3.4. Effect on Endocrine System .......................... 222 3.5. Conclusion ....................................... 223

4. Gastrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 223 4.1. Peripheral Effects .................................. 225 4.2. Central Effects .................................... 225 4.3. Endocrine Effects .................................. 226 4.4. Conclusion ....................................... 226

5. Motilin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 226 5.1. Distribution in the Nervous System . . . . . . . . . . . . . . . . . . . .. 226 5.2. Peripheral Effects .................................. 227 5.3. Central Action .................................... 227

Contents xxi

5.4. Endocrine Action .................................. 227 5.5. Conclusion ....................................... 227

6. Bombesin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 227 6.1. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 228 6.2. Peripheral Effects .................................. 228 6.3. Central Effects .................................... 228 6.4. Endocrine Effects .................................. 228 6.5. Conclusion ....................................... 229

7. Angiotensin .......................................... 229 7.1. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 230 7.2. Peripheral Action .................................. 231 7.3. Central Action .................................... 231 7.4. Conclusion ....................................... 232

8. Pancreatic Polypeptide .................................. 232 8.1. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 232 8.2. Peripheral Effect. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 234 8.3. Central Effects .................................... 234 8.4. Conclusion ....................................... 235

9. Insulin .............................................. 235 9.1. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 235 9.2. Conclusion ....................................... 236 References ........................................... 236

Chapter 11

Peptidergic Systems Peter Schotman, Loes H. Schrama, and Philippa M. Edwards

1. Introduction .......................................... 243 2. Anatomic Considerations Relevant to the Role of Peptides as Neu-

rohormones .......................................... 245 3. Localization of Peptidergic Systems ........................ 247

3.1. General Considerations .............................. 247 3.2. Peptides of Pituitary Origin ........................... 247 3.3. Peptides of Hypothalamic Origin ....... . . . . . . . . . . . . . . .. 249 3.4. Peptides Originating in Extrahypothalamic Brain and of Uncertain

Origin ................................... . . . . . . .. 255 3.5. Peptides in Spinal Cord and Peripheral Nerves ............ 257

4. Peptides as Neuroregulators .............................. 258 5. Interactions between Peptidergic and Aminergic Systems ........ 260

5.1. Dopaminergic Systems .............................. 260 5.2. Noradrenergic Systems .............................. 262 5.3. Serotonergic Systems ............................... 263

6. Interaction between Peptidergic and Nonmonoaminergic Systems ............................................. 263 6.1. Cholinergic Systems ................................ 263

xxii Contents

6.2. Amino Acid Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 264 6.3. Peptide-Peptide Interactions ................... . . . . . .. 264

7. Coexistence of Peptides and Other Agents ................... 265 8. Biochemical Effects .................................... 266

8.1. Receptors and Second Messengers ..................... 266 8.2. Trophic Functions of Peptides . . . . . . . . . . . . . . . . . . . . . . . .. 270 8.3. RNA and Protein Metabolism ......................... 271

9. Final Comments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 274 References ........................................... 275

Chapter 12

Neurosecretion S. Arch and H. Gainer

1. Introduction .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 281 2. Morphology .......................................... 283 3. Electrophysiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 286 4. Synthesis of Neurosecretory Products. . . . . . . . . . . . . . . . . . . . . .. 288 5. Axonal Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 297 6. Secretion ............................................ 298 7. Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 302

References ............. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 303

Chapter 13

Control of Monoamine Synthesis by Precursor Availability Candace J. Gibson

1. Introduction .......................................... 309 2. Plasma Amino Acid Composition and Brain Precursor

Concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 309 2.1. Sources of Circulating Tryptophan and Tyrosine ........... 309 2.2. Brain Uptake of Tryptophan and Tyrosine. . . . . . . . . . . . . . .. 312 2.3. Hormonal Influences on Plasma Amino Acid Pattern. . . . . . .. 313

3. Monoamine Biosynthetic Pathways. . . . . . . . . . . . . . . . . . . . . . . .. 314 3.1. Tryptophan Availability and Serotonin Synthesis ........... 315 3.2. Tyrosine Availability and Catecholamine Synthesis ......... 316 3.3. Requirements for Precursor Control of Monoamine

Synthesis ........................................ 319 4. Consequences of Precursor Control of Monoamine Synthesis ..... 319 5. Future Research ..................................... " 321

References ........................................... 322

Contents

Chapter 14

Cerebral Subsystems and Isolated Tissues Henry McIlwain

xxiii

1. Introduction .......................................... 325 2. Preparative Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 326

2.1. Obtaining the Isolate Minimally Altered . . . . . . . . . . . . . . . . .. 327 2.2. Choice and Criteria of Preparative Methods . . . . . . . . . . . . . .. 327 2.3. Alternative Methods ................................ 328 2.4. Incubation and Superfusion Techniques . . . . . . . . . . . . . . . . .. 329

3. Types of Observations Feasible ........................... 330 3.1. Metabolic Responses to Applied Agents ................. 330 3.2. Neurotransmitter Synthesis, Metabolism, and Output. . . . . . .. 330 3.3. Electrical Responses to Stimulating Agents ............... 331 3.4. Histological Examination of Isolates .................... 331

4. Neocortex ........................................... 332 5. Piriform Lobe: Olfactory Cortex and Lateral Olfactory Tract ..... 332 6. Hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 333

6.1. Dentate Gyrus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 334 6.2. The CAl Region ................................... 334 6.3. The CA3 Region ................................... 336 6.4. Long-Lasting Potentiation of Synaptic Transmission in Hippo-

campal Preparations ................................ 336 7. Optic Tract, Lateral Geniculate, and Superior Colliculus . . . . . . . .. 337 8. Other Systems ........................................ 338 9. Outlook ............................................. 339

References ........................................... 339

Chapter 15

Memory Bernard W. Agranoff

1. Introduction .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 343 1.1. The Role of Macromolecular Synthesis in Behavior-Interven-

tive and Correlative Approaches ....................... 343 1.2. Further Progress in the Role of Macromolecular Synthesis in Me­

diation of LTM Formation . . . . . . . . . . . . . . . . . . . . . . . . . . .. 344 2. Recent Progress in Biochemical Approaches to Behavior ........ 345

2.1. A Phyletic Sampling ................................ 345 2.2. Reduced Systems .................................. 346 2.3. Imprinting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 348 2.4. Kindling ......................................... 348 2.5. Interventive Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 349 2.6. Correlative Changes ................................ 350 2.7. Neurochemical Studies on Memory in Humans ............ 351 References ........................................... 353

xxiv Contents

Chapter 16

Neurochemical Correlates of Learning Impairment Yasuzo Tsukada

1. Introduction .......................................... 357 2. Strategies for Neurochemical Studies ....................... 358

2.1. Correlative Studies ................................. 358 2.2. Changes of Learned Behavior Caused by Administration of Met-

abolic Inhibitors or Experimental Brain Damage ........... 359 2.3. Isolation and Identification of Memory Substances ......... 363 2.4. Neurochemical Correlates of Learning Impairment in Animals

with Maldeveloped Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 364 3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 370

References ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 371

Chapter 17

Behavioral and Neurochemical Effects of ACTH Willem Hendrick Gispen and Henk Zwiers

1. Introduction .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 375 2. ACTH .............................................. 375

2.1. ACTH: Peptide Hormone and Neuropeptide .............. 375 2.2. ACTH as a Messenger .............................. 376

3. ACTH and Behavior in Experimental Animals and Man ......... 378 3.1. Conditioned Avoidance Behavior . . . . . . . . . . . . . . . . . . . . . .. 378 3.2. The Stretching and Yawning Syndrome ............ . . . . .. 381 3.3. Excessive Grooming ................................ 381 3.4. Sexual Behavior ................................... 388 3.5. Social Behavior. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 389 3.6. Behavioral and Clinical Studies in the Human ............. 390 3.7. Aging ........................................... 391

4. Neurochemical Mechanism of Action of ACTH ............... 392 4.1. Neurotransmitters .............. . . . . . . . . . . . . . . . . . . .. 393 4.2. Cyclic AMP ...................................... 394 4.3. Protein Phosphorylation ............................. 395 4.4. Lipid Phosphorylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 399 4.5. Synaptic Plasma Membrane Fluidity .................... 401

5. Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 402 References ..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 403

Chapter 18

Pain Transmission Tony L. Yaksh

1. Pain-Transmitting System 1.1. Peripheral Afferents

413 413

Contents xxv

1.2. Ascending Pathways by Which High-Intensity Stimulation Gains Access to Brain Centers ............................. 423

1.3. Supraspinal Systems in Pain Transmission . . . . . . . . . . . . . . .. 425 1.4. Summary of the Rostral Projection System ............... 430

2. Modulatory Systems That Control the Processing of Sensory-Evoked Activity ............................................. 432 2.1. Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 432 2.2. Descending Modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 433 References ........................................... 436

Chapter 19

The Neurochemical Study of Sleep Antonio Giuditta, Carla Perrone Capano, and Gigliola Grassi Zucconi

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 443 2. A Brief Outline of the Biology of Sleep . . . . . . . . . . . . . . . . . . . . .. 444 3. Hypotheses on the Functions of Sleep ...................... 447 4. Possible Approaches in the Neurochemical Study of Sleep ....... 448

4.1. Deprivation Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 448 4.2. Studies during Sleep ................................ 449

5. Sleep Neurochemistry .................................. 450 5.1. Energy and Intermediary Metabolism ................... 450 5.2. Amino Acids and Proteins. . . . . . . . . . . . . . . . . . . . . . . . . . .. 458 5.3. Nucleic Acids ..................................... 464

6. Sleep-Inducing Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 467 7. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 470

References .......... _ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 473

Chapter 20

Composition of Intraocular Fluids and the Microenvironment of the Retina Laszlo Z. Bito

1. Introduction ......................................... 477 2. Relevant Literature and the Scope of This Chapter ............ 478 3. The Intraocular Fluid Compartments. . . . . . . . . . . . . . . . . . . . . .. 478 4. Definitions and Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 479 5. Concentration Gradients within the Intraocular Fluid

Compartments ....................................... 481 6. The Transport Function of the Blood-Ocular Barrier Systems . . .. 482 7. Species Differences and the Reliability of Information on Human In-

traocular Fluids ...................................... 483 8. The Concentration of Major Solutes in Mammalian Intraocular Fluids

and in the Retinal Microenvironment . . . . . . . . . . . . . . . . . . . . . .. 483 8.1. Sodium, Chloride, and Bicarbonate .................... 483 8.2. Potassium ....................................... 486

xxvi Contents

8.3. Calcium and Magnesium ............................ 486 8.4. Inorganic Phosphate ............................... 489 8.5. Glucose and Lactic Acid ............................ 489 8.6. Ascorbic Acid .................................... 492 8.7. Amino Acids ................ '. . . . . . . . . . . . . . . . . . . .. 494 8.8. Osmolality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 496 8.9. Soluble Proteins and Enzymes. . . . . . . . . . . . . . . . . . . . . . .. 497

9. The Homeostasis of the Microenvironment of the Mammalian Retina ............................................. 499

10. The Microenvironment of the Avian Retina and Its Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 499

11. Recommendations for the Composition of Artificial Physiological So-lutions for Retinal Research ............................. 500

12. Conclusions ......................................... 502 References .......................................... 503

Chapter 21

Retina Nicolas G. Bazan and T. Sanjeeva Reddy

1. Introduction ......................................... 507 2. Cellular Organization .................................. 509 3. Photoreceptor Cells ................................... 512 4. Chemical Composition and Metabolism. . . . . . . . . . . . . . . . . . . .. 513

4.1. Nucleic Acids .................................... 514 4.2. Proteins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 514 4.3. Carbohydrates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 516 4.4. Lipids .......................................... 517

5. Neurotransmitter Metabolism ............................ 532 5.1. Acetylcholine .................................... 535 5.2. GABA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 537 5.3. Other Amino Acid Neurotransmitters. . . . . . . . . . . . . . . . . .. 538 5.4. Dopamine ....................................... 538 5.5. Serotonin ....................................... 539 5.6. Neuropeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 539

6. Cyclic Nucleotide Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . .. 541 6.1. Cyclic Nucleotides ................................ 541 6.2. Guanylate and Adenylate Cyclases .................... 541 6.3. Dopamine-Sensitive Adenylate Cyclase ................. 541 6.4. Phosphodiesterase ................................. 543

7. Retinoid Binding Proteins in Retina . . . . . . . . . . . . . . . . . . . . . . .. 543 8. Renewal of Visual Cells ................................ 545 9. Effect of Light on Retina ............................... 546

10. Axoplasmic Transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 547 1 I. Nutritional Studies .................................... 548

11.1. Essential Fatty Acid Deficiency ...................... 548

Contents xxvii

11.2. Vitamin E Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 548 11.3. Vitamin A Deficiency ............................. 549 11.4. Taurine Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 550 11.5. Zinc Deficiency .................................. 550

12. Effect of Ischemia .................................... 550 13. Diabetic Retinopathy .................................. 551 14. Retinal Degeneration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 551

14.1. Carbohydrate Metabolism .......................... 552 14.2. Protein and Nucleic Acid Metabolism ................. 552 14.3. Lipid Peroxides .................................. 553 14.4. Cyclic Nucleotide Metabolism ....................... 554 14.5. Gyrate Atrophy .................................. 554

15. Retinal Regeneration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 555 16. Conclusions and Perspectives ............................ 556

References .......................................... 559

Chapter 22

Vision Hitoshi Shichi

1. Introduction: Anatomy and Physiology of the Retina . . . . . . . . . . .. 577 2. Photoreceptors .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 579

2.1. Assembly and Breakdown . . . . . . . . . . . . . . . . . . . . . . . . . . .. 579 2.2. Structure of Disk Membranes ......................... 581 2.3. Properties of Disk Membranes. . . . . . . . . . . . . . . . . . . . . . . .. 582

3. Rhodopsin ........................................... 584 3.1. Chemical Properties of the Opsin Protein. . . . . . . . . . . . . . . .. 584 3.2. Physical Properties of the Opsin Protein ................. 586 3.3. Chromophore and Photochemistry. . . . . . . . . . . . . . . . . . . . .. 587

4. Visual Transduction .................................... 592 5. Neurotransmitters in the Retina ........................... 596

References ........................................... 598

Chapter 23

Cell Cultures L. Hertz, B. H. J. Juurlink, and S. Szuchet

1. Introduction .......................................... 603 2. Principles Used to Obtain Monotypic Cultures ................ 604

2.1. Cell Lines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 604 2.2. Primary Cultures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 606

3. Astrocytes ........................................... 613 3.1. Primary Cultures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 613 3.2. Cell Lines ....................................... , 621

xxviii Contents

4. Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 624 4.1. Neuronal-Glial Cocultures ........................... 624 4.2. Monotypic Primary Cultures of Neurons ................. 624 4.3. Cell Identity and Cell Markers. . . . . . . . . . . . . . . . . . . . . . . .. 628 4.4. Neurochemical Use of Primary Cultures of Neurons ........ 631 4.5. Neuronal Cell Lines ................................ 633

5. Oligodendrocytes ...................................... 634 5.1. Strategies to Obtain Monotypic Cultures of

Oligodendrocytes .................................. 634 5.2. Procedures for Cell Isolation . . . . . . . . . . . . . . . . . . . . . . . . .. 635 5.3. Establishment of Oligodendrocyte Cultures from Cells Isolated

by Gradient Centrifugation ........................... 639 5.4. Properties of Cultured Oligodendrocytes ................. 645 5.5. Cell Lines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 650

6. Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 651 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 652

Index ................................................. 663