Neurochemistry of Abused Drugs

164 Pages·2007·3.4 MB·English

by  Steven B. Karch MD FFFLM

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Half Title Page
Neurochemistry
of
Abused Drugs
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Title Page
Neurochemistr y
of
Abused Drugs
Edited by
Steven B. Karch, MD, FFFLM
Consultant Pathologist and Toxicologist
Berkeley, California
Boca Raton London New York
CRC Press is an imprint of the
Taylor & Francis Group, an informa business
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Library of Congress Cataloging-in-Publication Data
Neurochemistry of abused drugs / [edited by] Steven B. Karch.
p. ; cm.
“A CRC title.”
Includes bibliographical references and index.
ISBN-13: 978-1-4200-5441-5 (hardcover : alk. paper)
ISBN-10: 1-4200-5441-4 (hardcover : alk. paper)
1. Drugs of abuse--Pathophysiology. 2. Drugs of abuse--Physiological effect. 3. Neurochemistry. 4.
Neurotoxicology. I. Karch, Steven B.
[DNLM: 1. Substance-Related Disorders--physiopathology. 2. Brain--drug effects. 3. Neurotoxicity
Syndromes--etiology. 4. Substance-Related Disorders--complications. WM 270 N4943 2007] I. Title.
Q11.N4889 2007
616.8’047--dc22 2007008113
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Contents
Chapter 1 The Dopamine Transporter and Addiction................................................................1
William M. Meil, Ph.D. and John W. Boja, Ph.D.
Chapter 2 Neurochemistry of Nicotine Dependence................................................................23
Darlene H. Brunzell, Ph.D.
Chapter 3 Neurochemical Substrates of Habitual Tobacco Smoking......................................39
Irina Esterlis, Ph.D., Suchitra Krishnan-Sarin, Ph.D., and Julie K. Staley, Ph.D.
Chapter 4 Neurochemical and Neurobehavioral Consequences of
Methamphetamine Abuse.........................................................................................53
Colin N. Haile, Ph.D.
Chapter 5 Neurochemical Adaptations and Cocaine Dependence...........................................81
Kelly P. Cosgrove, Ph.D. and Julie K. Staley, Ph.D.
Chapter 6 Neuropsychiatric Consequences of Chronic Cocaine Abuse................................109
Deborah C. Mash, Ph.D.
Chapter 7 Neurobiology of 3,4-Methylenedioxymethamphetamine
(MDMA, or “Ecstasy”)..........................................................................................119
Michael H. Baumann, Ph.D. and Richard B. Rothman, M.D., Ph.D.
Index..............................................................................................................................................143
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Preface
The first reports of neurological disease complicating drug abuse were published almost as soon
as purified cocaine and morphine became abundant and cheap in the late 1800s. Today, neurological
complaints are among the most common manifestations of drug abuse. At the molecular level,
experimental studies have provided some surprising insights into the effects of drug abuse on the
brain and plausible explanations for some types of drug toxicity. For example, evidence is emerging
that nitric oxide formation plays an important role in cocaine neurotoxicity. Mice sensitized to
cocaine administration initially tolerated doses of cocaine that became lethal after less than a week,
but pretreatment with agents that inhibit nitric oxide synthetase completely abolished the sensiti-
zation process, and all test animals survived. Whether similar changes occur in humans remains to
be determined.
All abused drugs, not just cocaine, activate immediate-early gene expression in the striatum,
although different drugs induce somewhat different changes. Most activate immediate-early gene
expression in several regions of the forebrain, including portions of the extended amygdala, lateral
septum, midline/intralaminar thalamic nuclei, and even the cerebral cortex. These changes are
especially striking in the case of cocaine. Postmortem studies have shown that, in humans, the
numbers of both D1 and D2 dopamine receptors are altered by cocaine use, even with relatively
low doses of cocaine. Strong evidence suggests that alterations in dopamine transmitters and
receptors play a key role in the process of cocaine addiction and toxicity, but clearly much more
is involved.
It has always been a puzzling question that the neurotoxic changes produced by some amphet-
amines share a strong resemblance with those seen in some degenerative disorders. The answer is
no longer quite so puzzling. They share a number of common targets, including the ubiquitin–pro-
teasome system, and both the ubiquitin–proteasome pathway and beta–arrestin are molecular targets
of neurotoxicity. This knowledge may very well result in treatments for both.
Even though the mu receptor was first cloned nearly two decades ago, opiate addiction remains
a major public health concern. However, the molecular mechanisms of opiate addiction are slowly
becoming understood. Many of the changes that occur in neurons exposed to morphine have been
known for some time, but not that much is known about the changes in gene expression that underlie
these effects. With the advent of microarray analysis and quantitative (real time) PCR, it is now
possible to examine the gene expression changes that occur during morphine withdrawal. The
possibility of safely and effectively treating addicts (and relieving pain) is a tempting target and
will, no doubt, occur in the near future.
The chapters of this book describe the Pandora’s box of addictions that now face our society
— cocaine, tobacco, methamphetamine, and MDMA. More importantly, they describe what is know
at this moment about the neurochemical substrates underlying these disorders. Progress in molecular
biology will be stunted until scientists understand the clinical presentations of the diseases they
are trying to characterize. Clinicians stand little chance of curing addiction until they understand
the underlying neurochemistry. One might say that this volume contains something for everybody.
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The Editor
Steven B. Karch, M.D., FFFLM, received his under-
graduate degree from Brown University. He attended grad-
uate school in anatomy and cell biology at Stanford Univer-
sity. He received his medical degree from Tulane University
School of Medicine. Dr. Karch did postgraduate training in
neuropathology at the Royal London Hospital and in cardiac
pathology at Stanford University. For many years he was a
consultant cardiac pathologist to San Francisco’s Chief
Medical Examiner.
In the U.K., Dr. Karch served as a consultant to the
Crown and helped prepare the cases against serial murderer
Dr. Harold Shipman, who was subsequently convicted of
murdering 248 of his patients. He has testified on drug
abuse–related matters in courts around the world. He has a special interest in cases of alleged
euthanasia, and in episodes where mothers are accused of murdering their children by the trans-
ference of drugs, either in utero or by breast feeding.
Dr. Karch is the author of nearly 100 papers and book chapters, most of which are concerned
with the effects of drug abuse on the heart. He has published seven books. He is currently completing
the fourth edition of Pathology of Drug Abuse, a widely used textbook. He is also working on a
popular history of Napoleon and his doctors.
Dr. Karch is forensic science editor for Humana Press, and he serves on the editorial boards
of the Journal of Cardiovascular Toxicology, the Journal of Clinical Forensic Medicine (London),
Forensic Science, Medicine and Pathology, and Clarke’s Analysis of Drugs and Poisons.
Dr. Karch was elected a fellow of the Faculty of Legal and Forensic Medicine, Royal College
of Physicians (London) in 2006. He is also a fellow of the American Academy of Forensic Sciences,
the Society of Forensic Toxicologists (SOFT), the National Association of Medical Examiners
(NAME), the Royal Society of Medicine in London, and the Forensic Science Society of the U.K.
He is a member of The International Association of Forensic Toxicologists (TIAFT).