Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence

514 Pages·1977·17.95 MB·English

by  E. Änggård

Handbuch der experilTIentellen
Phartnakologie
Vol.45/11
Heffter-Heubner New Series
Handbook of ExperilTIental
Phartnacology
Herausgeber Editotial Board
G. V. R. Born, Cambridge . O. Eichier, 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.Erdös
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 II
Amphetamine, Psychotogen, and
Marihuana Dependence
Contributors
E.Änggard . W.L.Dewey· J.D.Griffith . L.-M.Gunne .
L.S.Harris . T.Lewander· W.R.Martin . R.K.Razdan·
J.W.Sloan
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,
P.O. Box 12390, Lexington, KY 40511jUSA
With 15 Figures
ISBN-13: 978-3-642-66711-4 e-ISBN-13: 978-3-642-66709-1
DOI: 10.1007/978-3-642-66709-1
Library of Congress Cataloging in Publication Data. Main entry under titIe: Drug addiction. (Handbook of experimental pharmacology:
New series; v. 45. pts. 1-2). Contributors, v. 2: E.Änggärd and others. Includes bibliographies and indexes. CONTENTS: I. Morphine,
sedative-hypnotic, aod aIeohol dependence. - 2. Amphetamine, psychotogen, and marihuana dependence. 1. Narcotic habit. 2. Drug ahuse.
3. Mental illness-Physiological aspects. I. Conrad, Harold, T. II. Martin, William R., 1921· III. Änggärd, E. IV. Series: Handbuch der
experimentellen Pharmakologie: New series; v. 45, pts. 1-2. QP905.H3 vol. 45, pts. 1-2 [RC566]615'.1'08s
[615'.782]77-24381
This work is subject to copyright. All rights aTe reserved, whether the whole or part of tbe material is concerned specifically those of
translation, reprinting, re-use of illustrations, broadcasting, reproduction hy photocopying macbine cr similar means, and storage in data
banks. Under § 54 of the German Law where copies are made for other than private use, a fee is payable to the publisher, the amount
of the fee to be determined by agreement with the publisher.
© by Springer·Verlag Berlin Heidelberg 1977
Softcover reprint of the hardcover I st edition 1977
Tbe use of registered names, trademarks, ete. in tbis publication does not imply, even in tbe absence of a speeifie statement, that sueh
names are exempt from the relevant protective laws and regulations and therefore free for general use.
2122/3130·543210
Contents
SECTION I
Arnphetarnine and Psychotogen Dependence
CHAPTER 1
General Pharmacology of Amphetamine-Like Drugs.
A. Pharmacokinetics and Metabolism. E. ÄNGGÄrd. With 7 Figures
A. Structure-Activity Relationships Among the Amphetamines 3
I. Effect of Aromatic Substitution . . . . . . . 3
II. Effect of Length of the Side Chain . . . . . 4
III. Effect of Substitution of the Primary Nitrogen 4
IV. Effect of Substitution of the Side Chain 4
V. Stereoisomers 5
B. Metabolism . . . . . . . . . . . . 5
I. Pathways of Metabolism .... 5
1. Hydroxylation of Amphetamine 8
2. Aliphatic Hydroxylation 9
3. Oxidative Deamination 9
4. N-Dealkylation ... . 12
5. N-Oxidation .... . 13
II. Stereoselectivity in Amphetamine Metabolism 13
III. Factors Influencing the Metabolism of Amphetamine 14
1. Species 14
2. Urinary pH . 15
3. Other Drugs 15
4. Other Factors 17
IV. Metabolism of Amphetamine in Dependent Subjects 18
C. Pharmacokinetics of Amphetamine 20
D. Relationship Between Blood Levels and Effect in Man 23
References 25
VI Contents
B. Effects of Amphetamine in Animals. T.LEWANDER
A. Introduction 33
B. Effects of Amphetamine on Neuronal Transmission 33
I. Biochemical Neuropharmacology 33
1. Adrenergic Transmission 33
a) Storage of CA 34
b) Uptake ofCA 38
c) Release of CA 40
d) Enzymatic Inactivation of CA 45
e) Synthesis ofCA . . . . . . 47
I) Turnover of CA . . . . . . 48
g) Uptake into and Release from Adrenergically Innervated Tissues
of Amphetamine Itself . . . . . . . . . 49
h) Amphetamine Metabolites and Tissue CA 50
i) Summary a11d Conclnsions 52
2. Serotoninergic (5HT) Transmission . . . . . 53
a) Storage of 5HT . . . . . . . . . . . . 53
b) Uptake of 5HT into Neurons and Platelets 54
c) Release of 5HT . . . . . . . . . . 54
d) Enzymatic Inactivation of 5HT 55
e) Synthesis and Turnover of Brain 5HT 55
I) Summary and Conclusions 56
3. Cholinergic Transmission . . . . . . . 56
4. Other Putative Transmittors ..... 57
5. Secondary Transmission; Cyclic Adenosine-3',5' -monophosphate
(cAMP) ......... 57
6. Summary and Conclusions . . . . . . . . . . . . . . . . . 58
11. Functional Neuropharmacology . . . . . . . . . . . . . . . . 58
1. Effects of Amphetamine on Peripheral Noradrenergically Innervated
and Other Tissues in Vivo and in Vitro ........ . 58
a) The Cat Nictitating Membrane and the Rat Inferior Eyelid 58
b) The Cat Iris ......... . 60
c) The Guinea Pig Vas Deferens 60
d) The Rabbit and Guinea Pig Intestines 60
e) The Guinea Pig Bladder . . . . . 61
,I) Other Peripheral Effects of Amphetamine Possibly Mediated
via Serotoninergic Mechanisms . . . . . 61
g) On Tachyphylaxis to the Sympathomimetic Effects of
Amphetamine and its Metabolites . . . . . 62
h) Summary of Conclusions . . . . . . . . . . . . . . . 64
2. Effect of Amphetamine on Sympathetic Ganglia . . . . 64
3. Effects of Amphetamine on the Nerve Impulse Activity of Single
Neurons in the Central Nervous System 65
a) Brain Stern Reticular Formation 65
b) Hypothalamus 65
c) Locus Ceruleus . . . . . . . 65
Contents VII
d) Substantia Nigra 66
e) Caudate Nucleus 66
f) Raphe Nuclei . . 67
g) Summaryand Conclusions 67
4. Functional Effecrs of Amphetamine Directly Related to Release
of DA, NA, and 5HT in the CNS . . . . . . . . . . . . . . 67
a) Amphetamine Induced Turning and Rotation in Rats and Mice
after Unilateral Lesions in the Dopamine Neuronal Systems 68
b) The Flexor Reflex . . . . 69
c) The Extensor Reflex . . . . . 69
d) Summaryand Conclusions 69
5. General Summary and Conclusions 69
C. Pharmacologic Effects of Amphetamine 70
I. Behavioral Effects of Amphetamine 70
1. Gross Behavior . . . . 70
a) Stereotyped Behavior 71
b) Motor Activity 81
c) Behavior Observed in the Open Field 93
d) Exploratory Behavior . . . . . . 94
e) Gross Behavior Effects in Birds . . 95
f) General Summaryand Conclusions 95
2. Social Behaviors . . . 95
a) Social Interaction . 96
b) Aggressive Behavior 96
c) Sexual Behavior 97
3. Conditioned and Operant Behaviors 98
a) The Conditioned Avoidance Response 98
b) Positively Reinforced Operant Behavior 108
c) Intracranial Self-Stimulation . . . . . 121
d) Self-Administration of Amphetamine in Animals 124
e) Amphetamine as an Aversive Stimulus 126
f) Maze Performance ...... 127
g) Conditioned Reflexes ....... 128
h) Miscellaneous Behavioral Studies 128
4. Effects of Amphetamine on Learning and Memory 129
a) Experiments on Learning and Memory 129
b) State-Dependent Learning .. . . . . . . 130
c) Summaryand Conclusions . . . . . . . . 131
11. Effects of Amphetamine on Food and Water Intake 131
1. Food Intake ............... 131
a) Amphetamine-Induced Anorexia ..... 131
b) Effects of Other Drugs on Amphetamine-Induced Anorexia 132
c) Effects of Brain Lesions on Amphetamine-Induced Anorexia 135
d) Effects ofBrain Stimulations on Amphetamine-Induced Anorexia 137
e) Effects of Amphetamine on the Electrical Activity of Neurons
Within the Hypothalamus .. . . . . . . . . . . . . . . 137
VIII Contents
f) Intraeerebral Injeetions of Amphetamine and Food Intake 137
g) Other Faetors Affeeting Amphetamine-Indueed Anorexia 137
h) Effeets of Chronie Administration of Amphetamine on F ood
Intake and Body Weight . . . . . . . . . . . . . . . . . 138
i) Summary of Proposed Meehanisms for the Anorexigenie Effeet
of Amphetamine 139
2. Hoarding Behavior 140
3. Water Intake 140
IU. Autonomie, Metabolie, and Endoerine Effeets of Amphetamine;
Amphetamine Toxieity ........ 141
1. Cardiovaseular Effeets of Amphetamine 141
a) Arterial Blood Pressure ..... 141
b) Effeet of Amphetamine on Pulmonary Cireulation 143
e) Effeet of Amphetamine on Cerebral Cireulation 143
d) Effeets of Surgieal Manipulations on the Pressor Response to
Amphetamine .................... 144
e) Effeets of Other Drugs on the Pressor Effeet of Amphetamine 144
f) Effeets ofRepeated Doses of Amphetamine on Blood Pressure 148
g) Summary and Conclusions 148
2. Respiratory Effeets of Amphetamine . 148
3. Amphetamine Indueed Salivation . 149
4. Body Temperature . . . . . . . . 149
a) Amphetamine-Indueed Hyperthermia 149
b) Effeets of Other Drugs on Amphetamine-Indueed Hyperthermia 150
e) Effeets ofBrain Lesions on Amphetamine-Indueed Hyperthermia 155
d) Other Faetors Influeneing Amphetamine-Indueed Hyperthermia 155
e) Physiologie Correlates to Amphetamine-Indueed Hyperthermia 156
f) Bioehemieal Correlates to Amphetamine-Indueed Hyperthermia 156
g) Effeets of Chronie Amphetamine Administration on the Hyper-
thermie Response . . . . . . . . 157
h) Amphetamine Indueed Hypothermia ........... 158
i) Behavior Thermoregulation . . . . . . . . . . . 158
j) Summary of Meehanisms Involved in Amphetamine-Indueed
Changes in Body Temperature . . . . . . . . . . . ... 159
5. Effeets of Amphetamine on General Metabolie Proeesses in Brain
and Peripheral Tissues . . . . . . . . . . . . . . . . 160
a) Oxygen Consumption . . . . . . . . . . . . . . . 160
b) Brain Adenosine Nueleotide and Phosphate Metabolism 161
e) Carbohydrate Metabolism 162
d) Lipid Metabolism 163
e) Protein Metabolism 164
f) Nucleie Aeid Metabolism 165
g) Miseellaneous Studies on General Metabolism 165
6. Endoerinologie Effeets of Amphetamine 165
a) Insulin ..... . 165
b) ACTH -Cortieosteroids 165
Contents IX
c) Growth Hormone 166
d) Prolactin 166
e) Pineal Gland Hormones 166
f) Thyroid Hormones 166
7. Toxicity of Amphetamine 166
a) Lethality After Amphetamine Administration 166
b) Factors of Importance for Amphetamine Induced Toxicity in
Aggregated and Isolated Mice and Rats . . . . . . . . . . . 167
c) Effects of Other Drugs on Am phetal11ine-Ind uced T oxicity in Mice
and Rats ....................... 169
d) Chronic Toxicity of Amphetamine ............ 173
e) Pathologic-Anatomical Findings in Amphetamine-Intoxicated
Animals . . . . . . . . . . . . . . . . . . . . 173
f) On the Cause of Death in Amphetamine Intoxication 174
g) SummaryandConclusions . . . . . . . . . . . . 175
IV. Miscellaneous Pharmacologic Effects on Amphetamine 176
1. Electroencephalographic Changes Caused by Amphetamine 176
2. Effects of Amphetamine on Seizure Susceptibility 177
3. Sleep and Wakefulness ................ 178
4. Amphetamine-Induced Analgesia ........... 179
5. Effects of Amphetamine on Physical Performance in Animals 179
D. Conclusion 180
Abbreviations Used 180
References 181
C. Effects of Amphetamines in Humans. L.-M.GuNNE. With 4 Figures
A. General Considerations .247
B. Effects of Single Doses .248
I. Mood .248
11. Performance .249
III. Wakefulness .250
IV. Anorexia .250
V. Analgesia · 251
VI. Libido . · 251
VII. EEG · 251
VIII. Evoked Responses .252
IX. REM SIeep .252
X. Cerebral Blood Flow .252
XI. Auditory Thresholds · 252
XII. CriticaI Flicker Frequency · 253
XIII. Pupil Size ..... · 253
XIV. Cardiovascular Effects · 253
XV. Respiration .254
x Contents
XVI. Metabolie Changes .254
XVII. Blood Cells · 255
XVIII. Various Smooth-Muscle Effects · 255
XIX. Hormones and Neurotransmitters · 255
C. Effects of Chronic Administration · 255
I. Mood .... · 255
11. Abuse Potential .257
III. Performance · 258
IV. Wakefulness · 258
V. Anorexia .259
VI. Analgesia .260
VII. Libido . .260
VIII. EEG .260
IX. REM Sleep .260
X. Cerebral Blood Flow, Auditory Thresholds, Critical Flicker
Frequency, and Pupil Size · 261
XI. Cardiovascular Effects . . . . . . . . . . . · 261
XII. Metabolie Effects ............ . · 261
XIII. Respiration, Blood Cells, and Smooth-Muscle Effects · 261
XIV. Hormones and Neurotransmitters · 261
D. Acute and Subacute Intoxication .262
I. Paranoid Psychosis .262
Il. Stereotyped Behavior .263
III. The Choreie Syndrome .263
IV. Excitation Syndrome .264
V. Dysautonomic Syndrome .264
VI. Cerebrovascular Accidents .265
E. Blockade of Amphetamine Effects · 265
References .266
CHAPTER 2
Amphetamine Dependence; Clinical Features. J.D.GRIFFITH
A. Naturally-Occurring Psychostimulants .277
I. Khat .277
11. Xanthines .277
III. Ephedrine .278
IV. Absinthe .278
V. Cocaine .278
B. Exogenous Phenethylamine Congeners .279
C. Synthetic Psychostimulants .279
I. Amphetamine and Methamphetamine .279
II. Other Amphetamine Congeners · 281
III. Psychodelic Amphetamines · 281