Handbook if Psychopharmacology

Volume 20

Psychopharmacology of the Aging Nervous System

Handbook of Psychopharmacology

SECTION I: BASIC NEUROPHARMACOLOGY Volume 1 Volume 2 Volume 3 Volume 4 Volume 5 Volume 6

Biochemical Principles and Techniques in Neuropharmacology Principles of Receptor Research Biochemistry of Biogenic Amines Amino Acid Neurotransmitters Synaptic Modulators Biogenic Amine Receptors

SECTION II: BEHAVIORAL PHARMACOLOGY IN ANIMALS Volume 7 Volume 8 Volume 9

Principles of Behavioral Pharmacology Drugs, Neurotransmitters, and Behavior Chemical Pathways in the Brain

SECTION III: HUMAN PSYCHOPHARMACOLOGY Volume 10 Volume 11 Volume 12 Volume 13 Volume 14

N euroleptics and Schizophrenia Stimulants Drugs of Abuse Biology of Mood and Antianxiety Drugs Affective Disorders: Drug Actions in Animals and Man

SECTION IV: BASIC NEUROPHARMACOLOGY: AN UPDATE Volume 15 Volume 16 Volume 17

New Techniques in Psychopharmacology Neuropeptides Biochemical Studies of CNS Receptors

SECTION V: BEHAVIORAL PHARMACOLOGY: AN UPDATE Volume 18 Volume 19 Volume 20

Drugs, Neurotransmitters, and Behavior New Directions in Behavioral Pharmacology Psychopharmacology of the Aging Nervous System

Volume 20

Psychopharmacology of the Aging Nervous System

Edited by

Leslie L. Iversen and Susan D. Iversen Neuroscience Research Centre

Merck Sharp &Dohme Research Laboratories Harlow, Essex, England

and

Solomon H. Snyder Departments of Neuroscience, Pharmacology, and Psychiatry

The Johns Hopkins University School oj Medicine

Baltimore, Maryland

PLENUM PRESS. NEW YORK AND LONDON

Library of Congress Cataloging in Publication Data

Psychopharmacology of the aging nervous system / edited by Leslie L. Iversen, Susan D. Iversen, and Solomon H. Snyder.

p. cm. -(Handhook of psychopharmacology; v. 20) Includes bibliographies and index. ISBN -13:978-1-4612-8252-5 e-ISBN -13:978-3-1-4613-0933-8 DOl: 10.1007/978-1-4613-0933-8

1. Alzheimer's disease-Pathophysiology-Handbooks, manuals, etc. 2. Dementia -Pathophysiology-Handbooks, manuals, etc. 3. Brain-Metabolism-Age fac­tors-Handbooks, manuals, etc. 4. Cholinergic mechanism-Handbooks, manuals, etc. 5. Psychopharmacology - HandLooks, manuals, etc. I. Iversen, Leslie L. I!. Iversen, Susan D., 1940- . II!. Snyder, Solomon H., 1938- . IV. Series. [DNLM: 1. Aging-drug effects. 2. Nervous System-rlrug effects. 3. Nervous System Diseases-in old age. QV 77 H236 sect. 5 v. 20] RM315.H345 1975 vol. 20 [RC523] 615'.78 s-de 19 [615'.78] DNLMIDLC 88-5929 for Library of Congress

© 1988 Plenum Press, New York Softcover reprint of the hardcover 1st edition 1988

A Division of Plenum Publishing Corporation 233 Spring Street, New York, N.Y. 10013

All rights reserved

clr

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

CONTRIBUTORS

YVES AGID, INSERM U. 289, 75013 Paris, France

PIERO ANTUONO, Division of Child Psychiatry, DepartmenL5 of Psychiatry, Phar­macology, Neuroscience, and Pediatrics, The johns Hopkins University School of Medicine, Baltimore, Maryland 21205

RAYMOND T. BARTUS, Department ofCNS Research, Lederll' Laboratories, Med­ical Research Division of Aml'rican Cyanamid, Pearl River, New York J0965, and New York UnivPrsit.'f Medical Center, New York, New York 10016

JOHN C. S. BREITNER, Department ojP,I~'Ychiatry, and Centerjor Studies on Aging and Human Development, Duke University Medical Center, Durham, North Carolina 27710

JOSEPH T. COYLE, Division of Child Psychiatry, Departments of Psychiatry, Phar­macology, Neuroscience, and Pediatrics, The johns Ilopkins Universit.'f School of Medicine, Baltimore, Maryland 21205

REGINALD L. DEAN, Department of CN,)' Research, I_ederle Laboratoril's, M niieal Research Division of Aml'rican Cyanamid, Pmrl River, New York 10965

J..J. HAGAN, CNS Pharmacology Laboratory, Organon BV, Oss, TIt(' Netherlands

CHRISTINE HOHMANN, Division of Child Psychiatry, Departmmts of Psychiatry, Pharmacology, Neuros('ience, and Pediatrics, Thl' johns Ilopkins Univl'rsity School of Medicine, Battimorl'. Maryland 21205

DAVID M. A. MAl\;N, Departml'nt oj Patlwlogy, Unzversity of Manchl'ster, Man­chester, England

RICHARD C. MOHS, Plychiatry Service, Veterans Administratio1l Medical Center, Bronx, New York 10468, and Departmmt of Psychiatry, MOl1l1t Sinai School of Medicine, New York, Nl'u' York /0029

R. G. M. MORRIS, Laboratory for Cognitive Neuroscintu', Department of Plun­macolol!,Y, University of Edinburgh Medical School, Edinburgh EH8 9jl, Scotland

l'

VI CONTRIBUTORS

B. P. H. POSCHEL, Department of Pharmacology, Warner-Lamberti Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105

M. ROSSOR, National Hospital and Institute of Neurology, London WC1, En­gland, and Department of Neurology, St. Mary's Hospital, London W2 1 NY, England

MERLE RUBERG, INSERM U. 289, 75013 Paris, France

B. J. SAHAKIAN, Section of Old Age Psychiatry, Department of Psychiatry, Institute of Psychiatry, University of London, London SE5 8AF, England

CLIFFORD B. SAPER, Departments of Pharmacological and Physiological Sciences and Neurology, and the Brain Research Institute, University of Chicago, Chi­cago, Illinois 60637

PREFACE

"Psychopharmacology of the Aging Nervous System" was selected as the topic for Volume 20 of the Handbook of PsychopharmacoloffY. Senile dementia is now widely recognized as a medical and social problem likely to reach epidemic proportions by the turn of the century. By that time it is esti­mated that almost 20% of the population in most developed countries will be over the age of 65 and at a conservative estimate 1 in 10 of them will suffer from a dementing illness.

Many symposia have appeared over the last few years describing the neuropathological and neurochemical deficiencies in Alzheimer's and other forms of dementia, the neuropsychological features of the disease, and attempts to treat it.

In this volume, we have selected topics and authors who are beginning to question some of the earlier assumptions and to ask different questions about dementia. In the first four chapters the neuropathology and neu­rochemistry of dementia are reevaluated. It is important to understand the relationship between the formation of amyloid plaques and neurofibrillary tangles, the progressive degeneration in cortex, and the neurochemical deafferentation of cortex. In particular, the possibility is considered that the most severe pathology is seen in a well-defined limbo/cortical circuitry known to be involved in mnemonic processing.

The growing interest in the genetic determinants of familial Alz­heimer's is reviewed. It is also recognized that detailed comparisons of the neural and psychological characteristics of the various degenerative dis­eases that impair cognitive processing may be valuable.

The challenge remains to provide effective new treatments capable of improving the deficient cognitive functioning in dementing diseases. In these efforts, methods for evaluating cognitive dysfunction in animals and man playa critical role and reviews have been included on the current status of such models in rodents, monkeys, and man. It is also important to explore a variety of drugs inf1uencing different aspects of neural function in the search for useful therapeutic agents. Improved eNS blood now,

Vll

vm PREFACE

oxygen and glucose availability, protection against toxic levels of excitatory amino acids, and attempts to restore neurotransmitter imbalances, all rep­resent possible approaches. The evaluation of novel cerebroactive or nootropic compounds represents an exciting challenge during the next stage of the battle against aging and degenerative diseases of the eNS.

L.L.1. s. D. I. s. H. s.

CONTENTS

CHAPTER 1

Neuropathological and Neurochemical Aspects of Alzheimer's Disease

DAVID M. A. MANN

1. Introduction .................................... 1 2. The Neuropathology of Alzheimer's Disease ....... 2

2.1. The Gross Changes of Alzheimer's Disease ... 2 2.2. Nerve Cell Loss in Alzheimer's Disease ...... 3 2.3. Degenerative Changes in Nerve Cells in

Alzheimer's Disease ........................ 6 2.4. The Senile Plaque ......................... 9 2.5. The Neurofibrillary Tangle. . . . . . . . . . . . . . . . . 12 2.6. Granulovacuolar Degeneration. . . . . . . . . . . . . . 17 2.7. The Hirano Body. . . . ... . .... . . . . .. . ... . . . . 18 2.8. Lewy Bodies and Alzheimer's Disease. . . . . . . . 18 2.9. Changes in Glial Cells... .... .. . ... . . .. ... . . 19

2.10. Changes in Blood Vessels. .... .. . . .. . ... .. . . 20 2.11. The Relationship between Senile Plaques,

Neurofibrillary Tangles, and Cerebrovascular Amyloid.................................. 20

3. Alzheimer-Type Changes in Conditions Other than Alzheimer's Disease .............................. 23 3.1. Nondemented Individuals of All Ages ....... 23 3.2. Down's Syndrome at Middle Age . . . . . . . . . . . . 23 3.3. Parkinson's Disease ........................ 24 3.4. Boxer's Encephalopathy and Other Conditions 26

4. Alzheimer's Disease and Patient A~e .............. 26 5. Biochemical Correlates of Pathological Changes .... 27

5.1. Neurotransmitter Changes. . . . . . . . . . . . . . . . . . 27 5.2. Changes in Protein Synthesis ............... 34

lX

x CONTENTS

6. Relationship between Plaques and Tangles and Nerve Cell Atrophy and Loss. ..... . .... . ......... 36

7. Relationship between Extent of Pathological Changes and Degree of Dementia ......................... 37 7.1. Gross and Light Microscopic Relationships ... 37 7.2. Relationships to Dementia at Ultrastructural

Level..................................... 40 8. Pathogenetic Considerations ...................... 40

8.1. Where Is the Site of the Primary Lesion in Alzheimer's Disease? Is It in the Cerebral Cortex or in the Subcortex? ................ 41

8.2. Is the SP or the NFT the Site of Primary Damage to Nerve Cells in Alzheimer's Disease? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

8.3. How Are SP Formed? ...................... 43 8.4. Where Does the Process of Alzheimer's

Disease Begin? ............................ 45 9. Concluding Remarks............................. 47

10. References...................................... 48

CHAPTER 2

Basal Forebrain Cholinergic Neurons and Alzheimer's Disease

CHRISTINE HOHMANN, PIERO ANTUONO, AND JOSEPH T. COYLE

1. Introduction .................................... 69 2. Basal Forebrain Cholinergic Systems .............. 71 3. Cholinergic Alterations in AD. .................... 77

3.1. Cortex.................................... 77 3.2. Basal Forebrain. . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 3.3. Cerebral Spinal Fluid AChE and Other

Peripheral Changes ........................ 84 4. Cholinergic Physiology ........................... 85

4.1. Behavioral Experiments .................... 85 4.2. Electrophysiological Studies. . . . . . . . . . . . . . . . . 86 4.3. Transsynaptic Consequences of Basal

Forebrain Cholinergic Lesions in Experimental Animals................................... 88

4.4. Cholinergic Pharmacotherapy in AD ........ 90 5. Conclusion...................................... 92 6. References...................................... 93

CONTENTS Xl

CHAPTER 3

Neurochemical Studies in Dementia

M. ROSSOR

I. I ntrod uction .................................... 107 1.1. Definition of Dementia ........... . . . . . . . . . . 108 1.2. Methodology of Human Neurochemistrv .... 109

2. Alzheimer's Disease .............................. III 2.1. Acetylcholine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III 2.2. Correlations of Cholinergic Deficit with

Cognitive Impairment. . . . . . . . . . . . . . . . . . . . . . 112 2.3. Norepinephrine and Dopamine ............. 113 2.4. Serotonin................................. 114 2.5. Amino Acids .............................. 115 2.6. Neuropeptides ............................ 116

3. Other Cortical Dementias ........................ 119 4. Subcortical Dementias . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

4.1. Parkinson's Disease and Progressive Supranuclear Palsy. . . . . . . . . . . . . . . . . . . . . . . . . 120

4.2. Huntington's Disease....................... 121 4.3. Depression.................. . . . . . . . . . . . . . . 121

5. Alcohol Dementia ............................... 121 6. Confusional States ............................... 122 7. Summary ....................................... 122 8. References...................................... 123

CHAPTER 4

Chemical Neuroanatomy of Alzheimer's Disease

CLIFFORD B. SAI'ER

1. Introduction: Relationship of Neural Connections and Neurotransmitters with Alzheimer Pathology. . . 131

2. Limbic and Cortical Connections and Neurotransmitters in Alzheimer's Disease. . . . . . . . . . 133 2.1. Distribution of Lesions in the Hippocampal

Formation ................................ 133 2.2. Distribution of Lesions in the Amygdala ..... 135 2.3. Distribution of Neocortical Lesions .......... 137 2.4. Neurotransmitters in Affected Limbic and

Corticocortical Connections ................. 140

xn

3. Brain Stem and Basal Forebrain-Cortical Connections and Neurotransmitters in Alzheimer's

CONTENTS

Disease ......................................... 141 3.1. Magnocellular Basal Nucleus. . . . . . . . . . . . . . . . 141 3.2. Thalamic Intralaminar Nuclei. .. . . . . . . .. . . . . ]43 3.3. Hypothalamus. . . . .. . . . . . . .. . . . . . . . . .. . . . . . 144 3.4. Brain Stem Monoamine Cell Groups ........ 146 3.5. Brain Stem Cholinergic Cell Groups. . . .. . . .. 147

4. Implications for the Pathogenesis and Treatment of Alzheimer's Disease. . . . .. . . . . . . . . . . . . .. . . . . . . . . . . 147

5. References 149

CHAPTER 5

Dementia in Parkinson's Disease

MERLE RUBERG AND YVES AGm

1. Introduction .................................... 157 2. Brain Lesions in Patients with Parkinson's Disease .. 158 3. Dementia and Lesions. . . . . . . . . .. . . . . .. . . . . . . . . .. . 160

3.1. Neuropathology........................... 160 3.2. Neurochemistry. .. . . . . . .. . . . . . . . . .. . . . . . .. 168

4. Parkinsonian Dementia. . . . . . . . . . . . . . . . . . . . . . . . . . . 177 4.1. Prevalence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 4.2. Characteristics of Parkinsonian

Psychopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 5. Symptoms and Lesions. . . .. . . . . . . . . .. . . . . ... . . . . . 184

5.1. Dopamine-Dependent Symptoms? ........... 184 5.2. Norepinephrine-Dependent Symptoms? ..... 188 5.3. Serotonin-Dependent Symptoms? ........... 188 5.4. Acetylcholine-Dependent Symptoms? ........ 189 5.5. Somatostatin-Dependent Symptoms? ......... 191

6. Conclusion...................................... 191 7. References...................................... 195

CHAPTER 6

Alzheimer's Disease: Genetic Theories of Etiology

JOl-l,N C. S. BREITNER

1. Introduction .................................... 207 2. The Genetic Hypothesis. .. . . . . . . . . .. . . . . . . .. . . . . . 207

2.1. Pedigree Studies of Presenile Disease .. ,..... 208 2.2. Studies of Pooled Proband Relatives. . .. . . .. . 209

CONTENTS xm

3. Critical Methodological Issues. . . . . . . . . . . . . . . . . . . . . 209 3.1. Diagnostic Heterogeneity ................... 210 3.2. Age-Dependent Onset. . . . . . . . . . . . . . . . . . . . . . 211 3.3. Resulting Ambiguity in Classical Twin and

Linkage Studies ........................... 211 4. Predicted Characteristics of Genetically Caused AD. 212

4.1. Gene Expression May Be Described by a Probability Distribution . . . . . . . . . . . . . . . . . . . . . 212

4.2. Expected Familial Incidence in a Rare Dominant Disorder ........................ 214

4.3. Expected Familial Incidence When a Dominant Predisposing Gene Is Common . . . . 214

4.4. Effect of Gene Frequency on Relative Risks for Proband versus Control Relatives ........ 215

4.5. Effects of Phenocopies in the Index Case Series. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

5. Review of Previous Studies ....................... 216 5.1. Approach................................. 216 5.2. Studies before 1955 ........................ 217 5.3. Studies after 1955 ......................... 218

6. Current Studies ................................. 221 6.1. The Minnesota State Hospital Studies ....... 222 6.2. The Duke Collaborative Studies. . . . . . . . . . . . . 226 6.3. The Baltimore Nursing Home Study ........ 227 6.4. The New York Studies ..................... 228 6.5. Autosomal Dominant Inheritance Suggested

by Both the Baltimore and New York Studies 229 7. Implications and Strategies for Future Research .... 230

7.1. Status of the Genetic Hypothesis ............ 230 7.2. Implications of Age-Dependent Expression of

AD ....................................... 231 7.3. Additional Research Strategies .............. 232

8. References...................................... 232

CHAPTER 7

The Cholinergic Hypothesis of Memory: A Review of Animal Experiments

J. J. HAGAN AND R. G. M. MORRIS

1. Introduction .................................... 237 2. Conceptual Issues ............................... 239 3. Methodological Issues. . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 4. Anatomy of Forebrain Cholinergic Pathways ....... 243

xw CONTENTS

5. Pharmacology of Central Cholinergic Neurons ..... 245 6. Pharmacological Evidence for Cholinergic

Involvement in Sensory, Attentional, and Motor Functions ....................................... 247

7. Pharmacological Studies of Rodent Learning and Memory........................................ 253 7.1. Discrimination Learning . . . . . . . . . . . . . . . . . . . . 253 7.2. Avoidance Learning ....................... 255 7.3. Spontaneous and Rewarded Alternation

Behavior .................................. 267 7.4. Maze Learning ............................ 270 7.5. Intracerebral I~ections .................... 276

8. Lesion Studies. . . .. . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . 281 8.1. Lesions of Ascending Cholinergic Projections . 281 8.2. Recovery of Function after Lesions .......... 290 8.3. Tissue Transplants. . . . . . . . . . . . . . . . . . . . . . . . . 292

9. Pharmacological Studies of Primate Memory ....... 294 9.1. Delayed Matching to Sample. ... . . . . . .. . . .. . 294 9.2. Primate Studies: Delayed Responding ....... 297 9.3. Other Behavioral Tasks .................... 299 9.4. Primate Studies: Conclusions ............... 301

10. Summary and Concluding Remarks.... . .......... 301 11. References...................................... 305

Chapter 8

Behavioral Models of Aging in Nonhuman Primates

REGINALD L. DEAN AND RAYMOND T. BARTUS

1. Introduction .................................... 325 2. Some Characteristics of Age-Related Behavioral

Deficits in Nonhuman Primates ................... 326 2.1. Behavioral Test Paradigms ................. 327 2.2. Recent Memory Impairment. . . . . . . . . . . . . . . . 328 2.3. Hypersensitivity to Visual Interference ...... 330 2.4. Discrimination Learning. . . . . . . . . . . . . . . . . .. . 331 2.5. Impairment in Reversal Learning ........... 333 2.6. Synopsis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

3. Relationship of Age-Related Behavioral Deficits in Nonhuman Primates to Humans. ....... .......... 334 3.1. Impairments in Recent Memory. . . . . . . . . . . . . 334 3.2. Hypersensitivity to Interfering Stimuli ....... 335

CONTENTS

3.3. Increased Perseveration/Behavioral Rigidity .. 3.4. Development of Human Memory Tests Based

on Nonhuman Primate Tasks .............. . 4. Relationship of Age-Related Behavioral Deficits in

Nonhuman Primates to Rodents ................. . 4.1. Recent Memory .......................... . 4.2. Hypersensitivity to Interference ............ . 4.3. Increased Perseveration/Behavioral Rigidity .. 4.4. Summary ................................ .

5. Possible Insights from Comparisons with Nonhuman Primates Given Discrete Brain Lesions ............ . 5.1. Frontal Cortex Lesions .................... . 5.2. Nucleus Basalis of Meynert Lesions ......... . 5.3. Hippocampal Lesions ..................... . 5.4. Amygdala Lesions ........................ . 5.5. Combined Lesions of Different Brain Regions .. 5.6. Summary ................................ .

6. Possible Insights from Drugs That Impair Performance on Memory Tasks in Young Subjects .. 6.1. Scopolamine and Other Anticholinergics .... . 6.2. Diazepam and Benzodiazepines ............ . 6.3. Tetrahydrocannabinol ..................... .

7. Drugs for Improving Age-Related Cognitive Losses: Current Status and Future Prospects ............. . 7.1. Neurotransmitter Modulation .............. . 7.2. Nootropics ............................... . 7.3. Neuropeptides ........................... .

8. Synthesis and Discussion ........................ . 9. References ..................................... .

CHAPTER 9

Cholinergic Drugs and Human Cognitive Performance

B. J. SAHAKIAN

xv

335

336

340 340 342 343 344

345 346 349 351 353 354 356

357 357 360 361

363 364 368 369 371 374

1. Introduction .................................... 393 2. The Effects of Cholinergic Agents on Processes

Involved in Learning and Memory in Experimental Animals ........................................ 394

3. The Effects of Cholinergic Agents on Processes Involved in Learning and Memory in Young Adult Human Subjects ................................. 398

xvi CONTENTS

4. Clinical Trials of Cholinergic Agents in Patients with Dementia of the Alzheimer Type or Aged Volunteers ...................................... 409

5. Implications and New Directions... ........... .... 418 6. References...................................... 421

CHAPTER 10

Treatment of Dementia with Vasoactive Drugs

RICHARD C. MOHS

1. Background and Rationale ....................... 425 1.1. Multiinfarct Dementia. .. . . . . .. . . . . . . .. . . ... 426 1.2. Degenerative Dementias .................... 428

2. Traditional Vasodilators. . . . . . . . . . . . . . . . . . . . . . . . . . 429 3. Recent Developments and Future Prospects. . . . . . . . 431

3.1. Calcium Channel Blockers .................. 431 3.2. Excitatory Amino Acid Antagonists. .. . . . . . . . 432

4. References...................................... 433

CHAPTER 11

New Pharmacological Perspectives on Nootropic Drugs

B. P. H. POSCHEL

1. Introduction .................................... 437 2. Known Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438 3. Goals of This Chapter ........................... 439 4. Distribution of Drugs in Brain .................... 440 5. Neuropsychopharmacological Studies.. . . .. . . . . . . .. 441

5.1. Aged Rat Quantitative EEG . . . . . . . .. . . . .. . . . 441 5.2. Therapeutic Window Discovered in

Quantitative EEG Studies . . . . . . . . . . . . . . . . . . . 443 5.3. Effects on New Learning and the Therapeutic

Window .................................. 445 5.4. Effects on Firing Rate of Neurons of the

Medial Septal Nucleus and the Area Ventral to the Globus Pallidus ...................... 447

5.5. Therapeutic Window Shown in Single-Neuron Firing Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448

5.6. Cerebral Intraventricular Administration of Pramiracetam and Piracetam and Effects on Single-Neuron Firing Rates. ... . . . . . . . . . . .. . 449

CONTENTS XVII

5.7. Functional Hippocampal Lesions and the Therapeutic Window . . . . . . . . . . . . . . . . . . . . . . . 450

6. Neurochemical Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . 453 7. Relationship to Endogenous Substances . . . . . . . . . . . . 455 8. Nootropic Drugs and Arguments for Supplementary

Choline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455 9. Clues to the Mode of Action of Nootropic Drugs ... 457

10. Some Thoughts on Clinical Trials. . . . . . . . . . . . . . . . . 461 II. Summary and Conclusion ........................ 463 12. References...................................... 464

Index ..................................................... 471