Psychotropic Agents: Part II: Anxiolytics, Gerontopsychopharmacological Agents, and Psychomotor Stimulants

795 Pages·1981·22.85 MB·English

by  L. H. Sternbach (auth.)

Handbook of
Experimental Pharmacology
Continuation of Handbuch der experimentellen Pharmakologie
Vol. 55III
Editorial Board
G. V. R. Born, London· A. Farah, Rensselaer, New York
H. Herken, Berlin· A. D. Welch, Memphis, Tennessee
Advisory Board
S. Ebashi . E. G. Erdos' V. Erspamer . U. S. von Euler' W. S. Feldberg
G. B. Koelle; O. Krayer· M. Rocha e Silva· 1. R. Vane' P. G. Waser
Psychotropic Agents
Part II: Anxiolytics,
Gerontopsychopharmacologica1 Agents,
and Psychomotor Stimulants
Contributors
C. Braestrup . P.B. Dews· S. Garattini . C. Giurgea . G. Greindl
W Haefely . H. Hauth· L.R. Hines· F. Hoffmeister· S. Hoyer
M.L. Jack· S.A. Kaplan· S. Kazda· DM. Loew· L. Pieri· P. Pole
S. Preat . L.A. Salazar· R. Samanin . R. Schaffner· c.R. Schuster
F. Seuter· L.H. Sternbach· J.M. Vigouret· J.E. Villarreal· T. Yanagita
Editors
F. Hoffmeister· G. Stille
Springer-Verlag Berlin Heidelberg New York 1981
Professor Dr. F. HOFFMEISTER
Bayer AG, Institut fUr Pharmakologie, Aprather Weg 18a, D-5600 Wuppertal I
Professor Dr. G. STILLE
Institut fUr Arzneimittel des Bundesgesundheitsamtes
StauffenbergstraBe 13, D-IOOO Berlin 30
With 77 Figures
ISBN-13: 978-3-642-67769-4 e-ISBN-13: 978-3-642-67767-0
DOl: 10.1007/978-3-642-67767-0
Library of Congress Cataloging in Publication Data. Main entry under title: Anxiolytics, gerontopsychophan <."ological
agents, and psychomotor stimulants. (Psychotropic agents; pt. 2) (Handbook of experimental pharmacology; v. 55/11).
Includes bibliographies and index. I. Tranquilizing drugs. 2. Geriatric psychopharmacology. 3. Stimulants. I. Braestrup, C.
II. Hoffmeister, Friedrich. III. Stille, Gunther, 1923-. IV. Series. V. Series: Handbook of experimental pharmacology;
v. 55/11. QP905.H3 vol. 55/11 [RM333]615'.ls 80-28013 [615'.7882].
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© by Springer-Verlag Berlin Heidelberg 1981
Softcover reprint of the hardcover 1s t edition 1981
The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific
statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.
Preface
This second volume continues the description of the psychotropic agents and discusses
anxiolytics, gerontopsychopharmacological agents, and psychomotor stimulants.
Of these groups of substances, most of this volume has been devoted to anxiolytics
as the authors have endeavored to convey as complete a picture as possible. The
editors are of the opinion that particular attention should be given to anxiolytics with
regard to their range of administration as this is the most frequently prescribed group
of psychotropic drugs. In contrast to neuroleptics and thymoleptics, anxiolytics are a
class of psychotropic drugs whose therapeutic effect can be recognized in animal
experiments to some extent. This, together with the analysis of the biochemical
mechanisms of their actions, permits a better understanding of material processes in
the brain accompanying the emotions: anxiety and tension.
For the first time in the history of the Handbook the editors have devoted a whole
chapter to gerontopsychopharmacological agents. In doing so they are also aware of
the risk they are taking, at least from a pharmacological point of view, as
gerontopsychopharmacological agents are an insufficiently defined and extremely
heterogeneous group of substances. The only denominator the various subgroups of
these agents have in common is that they are given in cases of dysfunctions,
disorders, and diseases of the brain occurring mainly in the elderly. Here the question
has been raised whether the therapeutic effects of all the substances in use are beyond
doubt, or whether they are, at least in part, given because there is a pressing need for
therapeutic intervention in these diseases of the elderly. Scientific psycho
pharmacology has long neglected research in this field with the result that, at present,
little is known about relevant basic pharmacological mechanisms. As a result, the
individual contributions are heterogeneous and should serve as a challenge to
motivate further studies in this field rather than seeing the information contained in
these chapters as being a complete description of this particular discipline. .
Psychomotor stimulants in our day playa limited role in therapy. The social
aspects of such stimulants, however, are enormous. With this in mind, the reader's
attention is drawn to the volume on drug dependence edited by MARTIN (45/11).
Independent of this knowledge of the effects of psychomotor stimulants, it is an
absolute must for the pharmacologist to be able to understand the cerebral
consequences of adrenergic, dopaminergic, and serotonergic stimulation.
Wherever possible and available, clinical pharmacology and therapeutic results
are included to insure a better understanding and to describe the therapeutic
relevance of pharmacological actions.
It was not the editor's intention to compile a textbook but rather to publish
the views and convictions of the individual scientist. The reader, therefore, should
VI Preface
not be surprised .when he finds redundant or even contradictory opinions on one
and the same theme in different chapters.
We believe that, in keeping with the tradition of the first volume, this second
volume on psychotropic agents should not only be used as a reference book, but
should also help to stimulate further research.
Wuppertal/Berlin F. HOFFMEISTER· G. STILLE
List of Contributors
Dr. C. BRAEsTRuP, Sct. Hans Mental Hospital, Dept. E, Psychopharmacological
Research Laboratory, DK-4000 Roskilde
Dr. P. B. DEWS, Department of Psychiatry, Laboratory of Psychobiology, Harvard
Medical School, 25 Shattuck Street, Boston, MA 02115jUSA
Professor Dr. S. GARATTINI, Istitudo di Ricerche Farmacologiche "Mario Negri",
Via Eritrea, 62, 1-20157 Milano
Professor Dr. C. GIURGEA, University of Louvain, Neuropharmacological
Department, U CB, Pharmaceutical Division, Rue Berkendael68, B-1 060 Bruxelles
Dr. G. GREINDL, University of Louvain, Neuropharmacological Department, UCB,
Pharmaceutical Division, Rue Berkendael 68, B-I060 Bruxelles
Dr. W.HAEFELY, Pharma Research Department, EHoffmann-La Roche&Co AG,
GrenzacherstraBe 124, CH-4002 Basel
Dr. H. HAUTH, Sandoz AG, Pharmazeutisches Department, CH-4002 Basel
Dr. L.R. HINEs, Hoffmann-LaRoche, Inc., Research Division, Nutley, NJ 07110jUSA
Professor Dr. F. HOFFMEISTER, Bayer AG, Institut flir Pharmakologie, Postfach
101709, D-5600 Wuppertal 1
Professor Dr. S. HOYER, Institut fUr Pathochemie und Allgemeine Neurochemie im
Zentrum Pathologie der UniversiHit Heidelberg, 1m Neuenheimer Feld 220-221,
D-6900 Heidelberg
Dr. M. L. JACK, Department of Pharmacokinetics and Biopharmaceutics, Hoffmann
La Roche, Inc., Nutley, NJ 07110jUSA
Dr. S. A. KAPLAN, Department of Pharmacokinetics and Biopharmaceutics, Hoff
mann-La Roche, Inc., Nutley, NJ 07110jUSA
Dr. S. KAZDA, Bayer AG, Institut fUr Pharmakologie, Postfach 101709, D-5600
Wuppertal 1
Dr. D. M. LOEW, Clinical Research, Sandoz, Inc., Hanover, NJ 07936jUSA
Dr. L.PIERI, Pharma Research Department, F.Hoffmann-La Roche&Co AG,
GrenzacherstraBe 124, CH-4002 Basel
Dr. P.POLC, Pharma Research Department, F.Hoffmann-La Roche&Co AG
GrenzacherstraBe 124, CH- 4002 Basel
VIII List of Contributors
Dr. S. PREAT, University of Louvain, Neuropharmacological Department, UCB,
Pharmaceutical Division, Rue Berkendael 68, B-I060 Bruxelles
Dr. L.A. SALAZAR, Instituto Miles de Terapeutica Experimental, Apdo Postal 22026,
MEX-Mexico 22, D.F.
Dr. R. SAMANIN, Istituto di Ricerche Farmacologiche "Mario Negri", Via Eritrea, 62,
1-20157 Milano
Dr. R. SCHAFFNER, Pharma Research Department, F. Hoffmann-La Roche&Co AG,
GrenzacherstraBe 124, CH-4002 Basel
Professor Dr. C.R. SCHUSTER, Department of Psychiatry, The University of Chicago,
950 East 59th Street, Chicago, IL 60637/USA
Dr. F. SEUTER, Bayer AG, Institut fUr Pharmakologie, Postfach 101709, D-5600
Wuppertal 1
Dr. L. H. STERNBACH, Hoffmann-La Roche Inc., Research Division, Nutley,
NJ 0711O/USA
Dr. J. M. VIGOURET, Preclinical Research, Pharmaceutical Division, Sandoz Ltd.,
CH-4002 Basel
Dr. J.E. VILLARREAL, Instituto Miles de Terapeutica Experimental, Apdo Postal 22026,
MEX-Mexico 22, D.F.
Dr. T. YA NAGITA, Preclinical Research Laboratories, Central Institute for Experi
mental Animals, 1433 Nogawa, J-213 Kawasaki
Contents
Anxiolytics
CHAPTER 1
The Chemistry of Anxiolytics. L. H. STERNBACH
A. Introduction . . . . . . . . 3
B. Classes of Antianxiety Agents. 3
I. Barbiturates . . . . . . 3
II. Propanediols . . . . . . 4
III. Compounds Belonging to Various Chemically Unrelated Classes. 5
IV. l,4-Benzodiazepines . 6
V. l,5-Benzodiazepines . 10
References. . 11
CHAPTER 2
General Pharmacology and Neuropharmacology of Benzodiazepine Derivatives.
W. HAEFELY, L. PIERI, P. POLC, and R. SCHAFFNER. With 5 Figures
Introduction. . . . . . . . . . 13
A. Acute Toxicity . . . . . . . . 14
I. Acute Toxicity in Man . . 14
II. Acute Toxicity in Animals. 14
III. General Comments on Acute Toxicity 14
B. Cardiovascular Effects . . . . . . . . . . 18
I. Blood Pressure, Heart Rate, and Other Hemodynamic Parameters 19
II. Arrhythmias. . . . . . . . . . . . . . . . . . . . . . . . 24
III. Isolated Myocardium. . . . . . . . . . . . . . . . . . . . 25
IV. Cardiovascular Responses to Central Nervous System Stimulation 26
V. Cardiovascular Responses to Behavioral Experiments. . . 27
VI. Cardiovascular Responses to Peripheral Stimulation . . . 28
VII. Cardiac and Vasoconstrictor Responses to Various Agents. 28
VIII. Conclusions. . . . 29
C. Effects on Respiration . . 30
I. Respiratory Control 30
II. Cough . . . . 33
III. Bronchospasm. 33
IV. Conclusions. . 34
x Contents
D. Effects on the Gastrointestinal System 34
I. Stomach . . . . . . . 34
II. Liver and Pancreas. . . 35
III. Gastrointestinal Motility 36
IV. Conclusions. . . . . . 37
E. Effects on Other Autonomic Funtions 38
F. Effects on Motor End Plate and Skeletal Muscle. 40
I. Neuromuscular Transmission In Vivo. 40
II. In Vitro Neuromuscular Preparations. 41
III. Effects on Invertebrate Musculature . 42
IV. Effects on Embryonic Muscles. . . . 42
V. Interaction with Neuromuscular Blockers 43
VI. Conclusions. . . . . . . . . . . . . 44
G. Effects on the Kidney and Body Fluid Electrolytes. 44
I. Urine. . . . . . . . . . . 44
II. Blood Electrolytes . . . . . . . . . 45
III. Sodium Current in Frog Skin . . . . 45
IV. Calcium Content of Synaptic Vesicles. 45
H. Effects on the Endocrine System. . . . . 45
I. Male and Female Sexual Hormones 45
II. Thyroid Hormones. 46
III. Pituitary Hormones . 46
IV. Conclusions. . . . . 47
I. Effects on Cell Metabolism. 47
I. Carbohydrates. . . . 47
II. Energy-Rich Phosphates 49
III. Lipids . . . . . 49
IV. Protein Synthesis. 50
V. Miscellaneous . 50
VI. Conclusions. . 51
J. Miscellaneous Effects 51
I. Nociception. . 51
II. Inflammation . 53
III. Food and Fluid Intake. 53
IV. Emesis . . . . . . 55
V. Body Temperature. 56
VI. Conclusions. . . . 56
K. Anticonvulsant Activity . 57
I. Acute Models of Epilepsy. 57
II. Chronic Models of Epilepsy . 68
III. Conclusions. . . . . . . . 70
L. Effects on Muscle Tone and Coordination 72
I. Subjective Methods of Evaluating Muscle Tone and Coordination 72
II. Objective Tests Believed to Record Muscle Tone. 73
III. Conclusions. . . . . . . . . . . . . . . . 76
M. Effects on Spontaneous and Induced Motor Activity . 76
I. Locomotor Activity . . . . . . . . . . . . 76
Contents XI
II. Exploratory Behavior. . . . . . . . . . . . . . 78
III. Effects on Drug-Induced Changes in Motor Activity 80
IV. Induced Head-Turning . . 82
V. Conclusions. . . . . . . 82
N. Benzodiazepines and Aggression. 82
I. Spontaneous Aggression . 83
II. Isolation-Induced Aggression in Mice. 85
III. Aggression in Grouped Male Mice. . 86
IV. Foot-Shock-Induced Aggression in Mice 86
V. Aggression Induced in Rats by Brain Lesions 86
VI. Brain Stimulation-Induced Aggression in Cats, Rats, and Monkeys 87
VII. Drug-Induced Aggression. . . . 88
VIII. Induction of Aggressive Behavior. . . . 88
IX. Conclusions. . . . . . . . . . . . . 88
O. Interaction with Other Centrally Active Agents 89
I. Synergism with "Centrally Depressant" Agents. 89
II. Antagonism with Centrally Active Agents . 91
III. Conclusions. . . . . . . . . . 93
P. Effects on Peripheral Nervous Structures . 94
I. Axonal Conduction . . . . . . . 94
II. Spontaneous and Evoked Activity in Sympathetic and Para-
sympathetic Nerves. . . . . . . . . . . . . 94
III. Synaptic Transmission in Sympathetic Ganglia. 95
IV. Dorsal Root Ganglia. . . 97
V. Conclusions. . . . . . . 97
Q. Effects on Invertebrate Neurons. 97
R. Effects of Spinal Cord Functions 99
I. Effects on Spinal Cord Activities Through a Supraspinal Site of
Action. . . . . . . . . . . 100
II. Effects Within the Spinal Cord. 101
III. Conclusions. . . . . . . . . 106
S. Effects on Dorsal Column Nuclei . . 106
T. Benzodiazepines and Evoked Potentials in the Brain 108
I. Limbic Structures . . . . . 109
II. Hypothalamus and Thalamus . . 110
III. Substantia Nigra. . . . . . . . 111
IV. Brain Stem Reticular Formation. 111
V. Lateral Vestibular Nucleus 111
VI. Visual System . 112
VII. Cerebral Cortex . . . . . 112
VIII. Conclusions. . . . . . . 113
U. Effects on Cortical and Subcortical Electroencephalogram (EEG) 114
I. Spontaneous EEG. . . . . 114
II. Arousal Reaction . . . . . . . . . . . . . 117
III. Hippocampal Theta-Rhythm . . . . . . . . 119
IV. Cortical Recruiting and Augmenting Response. 120
V. Caudate Spindles. . . . . . . . . . . . . . 121