Drug Addiction I: Morphine, Sedative/Hypnotic and Alcohol Dependence

767 Pages·1977·33.18 MB·English

by  W. R. Martin (auth.)

Handbuch der experimentellen
Phannakologie
Vol. 45/1
Heffter-Heubner New Series
Handbook of Experimental
Phannacology
H erausgeber Editorial Board
G.V.R.Born, Cambridge· O.Eichler, Heidelberg
A. Farah, Rensselaer, NY . H. Herken, Berlin
A.D. Welch, Memphis, TN
Beirat Advisory Board
E.J.Ariens . Z.M.Bacq . P.Calabresi· S.Ebashi· E. G. Erdos
V. Erspamer . U. S. von Euler· W. S. Feldberg· G. B. Koelle· O. Krayer
T.A.Loomis . H.Raskova· M.Rocha e Silva· F.Sakai· J.R.Vane
P. G. Waser . W. Wilbrandt
Drug Addiction I
Morphine, Sedative/Hypnotic and
Alcohol Dependence
Contributors
H.T.Conrad· H.F.Fraser· C.W.Gorodetzky· D.R.lasinski
P.Kielholz· D.Ladewig· W.R.Martin· N.K.Mello
lH.Mendelson· l.W.Sloan . C.M.Smith
Editor
William R. Martin
Springer-Verlag Berlin Heidelberg New York 1977
WILLIAM R.MARTIN, M.D., U.S. Department of Health, Education, and Welfare,
Public Health Service, National Institute on Drug Abuse, Addiction Research
Center, Lexington, KY 40511, USA
With 24 Figures
ISBN-13: 978-3-642-66614-8 e-ISBN-13: 978-3-642-66612-4
DOl: 10.1007/978-3-642-66612-4
LIbrary of Congress Catalogmg In PublIcatIOn Data Mam entry under tItle Drug addIctIOn (Handbook of expenmental pharmacology
New senes, v 45, pts 1-2) Contnbutors, v 2 E Angg~rd and others Includes blbhographles and lOdexes CONTENTS 1 MorphlOe,
sedatIve-hypnotIc, and alcohol dependence - 2 Amphetamme, psychotogen, and marIhuana dependence 1 Narcotic hahlt 2 Drug abuse
3 Mental Illness-PhysIOlogIcal aspects I Conrad, Harold, T II MartlO, WIlham R, 1921-III Anggltrd, E IV Senes Handbuch der
expenmentellen Pharmakologle New senes, v 45, pts 1-2 QP905 H3 vol 45, pts. 1-2 [RC566] 615' 1'08s
ISBN 0-387-08170-4 (v 1) [615' 782] 77-24381
ThIS work IS subject to copYrIght All fIghts are reserved, whether the whole or part of the materIal IS concerned specIfically those of
translatIOn, repnntIng, fe-use of IllustratIOns, broadcastmg, reproductIOn by photocopymg machme or simIlar means, and storage 10 data
banks Under § 54 of the German Law where cOpies are made for other than pnvate use, a fee IS payable to the pubhsher, the amount
of the fee to be determIned by agreement with the pubhsher
© by Spnnger-Verlag Berhn HeIdelberg 1977
Softcover reprint of the hardcover 1st edition 1977
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 volume addresses the general problem of drug addiction from several points of
view, which are in some ways quite unique and different from other areas of
pharmacology. Drug addiction is closely associated with criminal behavior. One of
the great and noble edifices of civilization is the philosophic and ethical view that
man is perfectible, and some believe that this can be achieved by providing the
appropriate circumstance or environment in which man can mature and be educated.
Some have postulated that drug abuse is a consequence of an inadequate or
pathologic set of socializing experiences or is a consequence of basic conflicts between
the values and accepted patterns of behavior of a subculture and that of a larger
culture. The degree to which man is malleable and perfectible by social forces is not
known nor do we know the true desirability of socializing individuals to the extent
that their behavior does not deviate from social norms. Some deviancy is essential for
innovation and creativity, and at times there may be difficulties in determining
whether an innovator or creator is exhibiting sociopathic behavior or not. This aspect
of drug addiction is inherently a matter of social values and ethics.
These problems have not been treated in depth in this volume. Rather the major
thrust of this volume is to explore the possibility that many drug abusers have
an organic dysfunction of the brain. In recent decades, the possibility that
mental illness is a consequence of improper functioning of the brain has gained
increasing acceptance. The discovery of malfunctioning brain mechanisms that are
responsible for behavioral pathology seems to be a goal achievable in the foreseeable
future. With the advances in the understanding of mental illness, pathologic brain
function and chemotherapy, it is unfortunate that the most prevalent and most
costly of all mental diseases, psychopathy, has received the least attention of the
neurobiologists.
It is hoped that this volume will stimulate the experimental therapists to become
more involved in the general problems of psychopathy and the particular problem
of drug abuse. The greater portion of this volume will be devoted to the description
of the effects of drugs of abuse on the function of the brain and body. Although
the state of the art at the present time does not permit definitive medical
treatment of either drug abusers or criminals, another major portion of this volume
will be devoted to methods and to description of endeavors that the pharma
cologists can make and have made in both treating and limiting drug abuse.
There are two conspicuous omissions in this volume, namely, chapters on
tobacco and cocaine. Tobacco was omitted because it was felt that it could not be
treated comprehensively within the limitation of this volume. Cocaine was omitted
because at the time this volume was formulated it was felt that knowledge about its
VI Preface
modes and sites of action in producing euphoria and psychotic behavior was not
well understood or even vigorously investigated and that most of our current
speculations about its central nervous system actions would be treated in the
sections on amphetamines and LSD-like hallucinogens.
The support that the National Institute of Mental Health, the National Institute
on Drug Abuse, and the President's Special Action Office for Drug Abuse Prevention
have given to the research of myself and other scientists at the Addiction Research
Center, as well as to many other scientists who have had an interest in problems
of drug abuse and whose works are cited in this volume, is gratefully acknowledged.
The views that are expressed in this volume do not, however, necessarily represent
the positions or views of these agencies or the Department of Health, Education
and Welfare.
Many people have contributed to this volume both directly and indirectly.
Mrs. BARBARA W. SMITH and Mrs. LULA H. MOORE, my dedicated secretaries, have
provided invaluable assistance in preparing and editing the chapters and
bibliographies. There will probably not be another quite so appropriate
circumstance where I will be able to express my gratitude to my teachers and
friends, Drs. K. R. UNNA, A. WIKLER, H. F. FRASER, and H. ISBELL, for shaping my
interests in pharmacology, drug abuse, and diseases of the mind.
This volume has evolved more slowly than I thought it would when I undertook
the task of editing it. I wish to express my gratitude to Prof. ALFRED FARAH for
selecting me as its editor and to him and the publisher for patiently allowing
this volume to evolve. It is only with the forebearance and encouragement of my
wife Catherine and my children Catherine, David, and Douglas that this task could
have been completed.
I would like also to apologize to our colleagues whose works have been omitted
on behalf of myself and the other contributors. In some areas the literature is so vast
that it could not have been comprehensively reviewed in this volume. Further, the
literature in the area of drug addiction is expanding rapidly and many of the
omissions of the more current works may reflect the difference in times that the
various chapter were completed.
Lexington, Kentucky, July 1977 WILLIAM R. MARTIN
Contents
SECTION I
Problems of Drug Dependence
CHAPTER 1
General Problems of Drug Abuse and Drug Dependence. W.R.MARTIN. With 1 Figure
A. Introduction 3
B. Cost of Abuse of Major Drugs (Economic, Social, and Health) 4
I. Narcotic Analgesics ................ 4
II. Sedative/Hypnotics and Minor Tranquilizers (Depressants) 5
III. Alcohol ............. 6
IV. Amphetaminelike Agents (Stimulants) 7
V. Hallucinogens ....... 8
VI. Cannabis, Marihuana, Hashish 8
VII. Summary and Conclusions 10
C. Legal and Regulatory Approaches to Minimizing Drug Abuse 11
I. Forces Influencing Federal Legislation . . . . . . . . 11
II. Summary of Laws of the United States Regulating Drugs of Abuse 13
D. Medical Treatment and Research Efforts 18
I. National Research Council 19
II. The Federal Government 20
1. Treatment ...... 20
2. Research ...... 24
III. Medical and Psychiatric Concepts of Addiction 24
1. Psychopathology ........... 25·
2. Sociologic Theories .......... 29
3. Tolerance, Dependence, and Conditioning 30
4. Heredity . . . 33
E. Conclusions . . . . . 34
Most Usual Abbreviations 35
References 35
VIII Contents
SECTION II
Morphine Dependence
CHAPTER 1
Neuropharmacology and Neurochemistry of Subjective Effects, Analgesia, Tolerance,
and Dependence Produced by Narcotic Analgesics. W.R.MARTIN and J.W.SWAN.
With 9 Figures
A. Introduction 43
B. Subjective States and Their Correlates 45
I. Introduction . . . . . 45
II. Subjective Effects in Man 46
1. Single Doses . . . . 46
2. Effects of Chronic Administration and Withdrawal 47
III. Mouse 48
IV. Rat 49
V. Cat ....... . 51
VI. Protracted Abstinence 51
VII. EEG Effects .... 51
VIII. Discussion and Conclusions 53
C. Analgesia and Pain . . . . . . . 54
I. Introduction . . . . . . . 54
II. Neuropharmacology of Pain and the Narcotic Analgesics 55
1. Peripheral Nerve and the Myoneural Junction 55
2. Spinal Cord . . . . . . . . . . . . 55
a) Segmental and Spinal Cord Reflexes 55
oc) Cat 55
{3) Dog .......... . 57
y) Rat .......... . 57
b) Spinal Cord Inhibitory Processes 58
3. Supraspinal Influences 58
4. Sensory Pathways ...... . 60
5. Discussion and Conclusions 62
III. Neurochemical and Neurohumoral Changes Associated with Analgesia 62
1. Introduction . 62
2. Acetylcholine 63
a) Analgesia 63
b) Guinea Pig Ileum and Other Isolated Tissues 64
c) BrainAChRelease . . 65
d) BrainACh Metabolism 66
3. Serotonin 66
Analgesia 66
Contents IX
4. NE and E . . . . . . . . . . . . . 68
a) Analgesia ........... 68
b) Interactions with Narcotic Analgesics 69
c) Metabolism ...... 69
ex) Dopamine p-Hydroxylase 69
p) Tyrosine Hydroxylase 70
y) Reserpine 70
£5) 6-0HDA 71
6) Pyragallol 71
() Isolated Tissue 71
5. Dopamine (DA) 71
6. Other Drugs Which Affect Indole and Catecholamine Metabolism 72
7. Cyclic AMP, Prostaglandins, and Polypeptides 73
8. Discussion and Conclusions 74
D. Tolerance and Physical Dependence 75
I. Introduction . . . . . . . 77
II. Definitions 77
III. Description of Tolerance and Dependence 75
1. Mouse 77
2~ 77
3. Guinea Pig 79
~~~ ~
~D~ ~
6. Monkey 81
7. Man 82
IV. Problems of Quantitating Tolerance and Physical Dependence 87
1. Tolerance . . . . . . . 87
a) Baseline Problem 87
b) The Syndrome Problem 88
c) Change in Effect . . . 88
d) Quantitation of Tolerance 89
2. Physical Dependence 89
a) Baseline Problem 89
b) Syndrome Problem 90
V. Neurophysiology 91
1. Isolated Tissues 91
2. Spinal Cord and Brain 93
VI. Neurochemical and Neurohumoral Changes 95
1. ACh ...... 95
2. EandNE 97
a) Adrenal Medulla 97
ex) Single Doses (Cat, Dog, Rat, Mouse, Rabbit) 98
p) Chronic Administration ..... 98
y) Abstinence (Rat, Dog, Rabbit, Man) . . . . 99
x
Contents
b) Brain ...................... . 100
a) Single Doses (Cat, Dog, Rat, Mouse) . . . . . . .. . 100
{3) Chronic Administration (Monkey, Cat, Dog, Rat, Mouse) . 101
y) Abstinence . . . . . . . . . . . . . . . . . 102
3. DA .......................... 103
a) Single Doses (Cat, Monkey, Rabbit, Mouse, Rat) .... 103
b) Chronic Administration (Rat, Mouse, Dog, Monkey, Man) . 104
c) Abstinence (Rat, Dog, Mouse) . . . 104
4. Serotonin . . . . . . . . . . . . . . . . . . . . .. 106
a) Single Doses (Cat, Dog, Rat, Mouse) . . . . . . . .. 106
b) Chronic Administration (Dog, Rat, Mouse, Rabbit, Man) 107
c) Abstinence .................... 107
5. Proteins, Polypeptides, Cyclic AMP, Prostaglandins, and GABA 110
VII. Theories of Tolerance and Physical Dependence 112
1. Neuronal and Neurohumoral Factors 112
2. General Theories . . . . . . 113
a) Homeostasis ..... . 113
b) Learning and Adaptation . 114
c) Reversible Changes 116
d) Persisting Changes 121
Single Cells 121
VIII. Summary and Conclusions 123
Abbreviations . 126
References . 127
CHAPTER 2
Assessment of the Abuse Potential of Narcotic Analgesics in Animals. W.R.MARTIN
and D.R.JASINSKI. With 2 Figures
A. Introduction ...... . 159
B. Reinforcing Properties 161
C. Pharmacologic Equivalence . 162
I. Autonomic, Somatomotor, and Behavioral Effects in Nondependent
and Dependent Animals . 162
II. Tolerance and Cross-Tolerance ..... . 163
III. Suppression Studies .......... . 163
IV. Direct Addiction and Precipitation Studies . . 164
D. Mouse .................. 166
I. Pharmacologic Profile ......... 166
II. Direct Addiction, Suppression and Precipitated Abstinence Studies 166
E. Rat ......... 167
I. Pharmacologic Profile 167
II. Self-Administration . 168
III. Suppression Studies 169
IV. Direct Addiction and Precipitation Studies . 170