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This page intentionally left blank
 HANDBOOK OF EXPERIMENTAL NEUROLOGY

Basic relevant information on methodologies used in neurological disease

models can be extremely hard to find. The Handbook of Experimental
Neurology contains 30 chapters from over 60 internationally recognized scien-
tists and covers every major methodology and disease model in the neuro-
sciences. The book is divided into two major sections: Part I deals with general
methodologies in neuroscience research covering topics from animal welfare
and ethical issues to surgical procedures, postoperative care, and behavioral
testing, while Part II covers every major disease model from traumatic brain
injury, ischemia and stroke, to CNS tumors, hydrocephalus, demyelinating dis-
ease, Parkinson’s, motor neuron disease, epilepsy, bacterial infection, and sleep
disorders. Delivering critical, up-to-the-minute, methodological information and
describing small-animal models for almost all major neurological diseases, this
book is written specifically for beginners and young scientists in neurosciences.
It will also serve as a cutting-edge reference for more experienced researchers.

D R . T A T L I S U M A K received his neurology training in the Helsinki University

Central Hospital. His Ph.D. was gained in experimental brain ischemia and
magnetic resonance imaging at the University of Massachusetts. His research
field is clinical and experimental stroke and magnetic resonance imaging. He
holds board certificates in neurology and healthcare administration in Finland.
He is currently an associate professor and Vice-Chairman at the Department of
Neurology, Helsinki University Central Hospital and the director of the
Experimental Magnetic Resonance Imaging Laboratory. Dr. Tatlisumak is
a Fellow of the American Heart Association. He is an awarded teacher and
holds a degree in teaching sciences.

D R . F I S H E R received his medical degree from the State University of

New York at Syracuse and then trained in medicine at the University of
Wisconsin and neurology at the Medical Center of Vermont. He has been at
the University of Massachusetts Medical School since 1978 and currently
holds the position of Professor and Vice-Chairman in the neurology depart-
ment. He performs clinical activities approximately 50% of the time with a
special emphasis on patients with cerebrovascular disorders and multiple
sclerosis. He has directed an animal stroke research laboratory for more
than 15 years that has emphasized the use of novel magnetic resonance
imaging techniques to evaluate stroke evolution and to assess therapeutic
interventions in vivo. He has participated in many clinical stroke trials as
a member of the steering committee. He has published extensively in both
of these areas with 190 peer-reviewed publications, and he has edited 10
textbooks. He has worked closely with the pharmaceutical industry in the
development of novel stroke therapies as well as in designing and implement-
ing clinical trials for acute stroke therapies.
HANDBOOK OF EXPERIMENTAL
NEUROLOGY
Methods and Techniques in Animal Research

edited by

TURGUT TATLISUMAK
Helsinki University Central Hospital

and
MARC FISHER
University of Massachusetts
cambridge university press
Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo

Cambridge University Press

The Edinburgh Building, Cambridge cb2 2ru, UK
Published in the United States of America by Cambridge University Press, New York
www.cambridge.org
Information on this title: www.cambridge.org/9780521838146

© Cambridge University Press 2006

This publication is in copyright. Subject to statutory exception and to the provision of

relevant collective licensing agreements, no reproduction of any part may take place
without the written permission of Cambridge University Press.

First published in print format 2006

isbn-13 978-0-511-24927-3 eBook (EBL)

isbn-10 0-511-24927-6 eBook (EBL)

isbn-13 978-0-521-83814-6 hardback

isbn-10 0-521-83814-2 hardback

Cambridge University Press has no responsibility for the persistence or accuracy of urls
for external or third-party internet websites referred to in this publication, and does not
guarantee that any content on such websites is, or will remain, accurate or appropriate.
 Contents

List of contributors page viii

Part I Principles and general methods 1
1 Introduction: Animal modeling – a precious tool for
developing remedies to neurological diseases
TURGUT TATLISUMAK AND MARC FISHER 3
2 Ethical issues, welfare laws, and regulations
DAVID WHITTAKER 6
3 Housing, feeding, and maintenance of rodents
ROBERT W. KEMP 19
4 Identification of individual animals
TURGUT TATLISUMAK AND DANIEL STRBIAN 33
5 Analgesia, anesthesia, and postoperative care
in laboratory animals
NAOYA MASUTOMI AND MAKOTO SHIBUTANI 40
6 Euthanasia in small animals
TURGUT TATLISUMAK 67
7 Various surgical procedures in rodents
R E N É R E M I E 75
8 Genetically engineered animals
CAROLINA M. MAIER, LILLY HSIEH, AND PAK H. CHAN 114
9 Imaging in experimental neurology
MARC FISHER, ENG H. LO, AND MICHAEL LEV 132
10 Safety in animal facilities
TARJA KOHILA 147
11 Behavioral testing in small-animal models: ischemic stroke
LARRY B. GOLDSTEIN 154
12 Methods for analyzing brain tissue
P Ä I V I L I E S I 173

v
vi Contents

13 Targeting molecular constructs of cellular function and injury

through in vitro and in vivo experimental models
ZHAO ZHONG CHONG, FAQI LI, AND KENNETH MAIESE 181
14 Neuroimmunology and immune-related neuropathologies
BAO-GUO XIAO AND HANS LINK 212
15 Animal models of sex differences in non-reproductive
brain functions
GEORGE T. TAYLOR, JUERGEN WEISS, AND FRANK ZIMMERMANN 239
16 The ependymal route for central nervous system gene therapy
ERICA BUTTI, GIANVITO MARTINO, AND ROBERTO FURLAN 257
17 Neural transplantation
STEPHEN B. DUNNETT, EDUARDO M. TORRES, MONTE A. GATES,
AND ROSEMARY A. FRICKER-GATES 269

Part II Experimental models of major neurological diseases 309

18 Focal brain ischemia models in rodents
FUHAI LI AND TURGUT TATLISUMAK 311
19 Rodent models of global cerebral ischemia
JULIA KOFLER AND RICHARD J. TRAYSTMAN 329
20 Rodent models of hemorrhagic stroke
FATIMA A. SEHBA AND JOSHUA B. BEDERSON 345
21 In vivo models of traumatic brain injury
RONEN R. LEKER AND SHLOMI CONSTANTINI 366
22 Experimental models for the study of CNS tumors
TAICHANG JANG AND LAWRENCE RECHT 375
23 Experimental models for demyelinating diseases
JASON M. LINK, RICHARD E. JONES, HALINA OFFNER,
AND ARTHUR A. VANDENBARK 393
24 Animal models of Parkinson’s disease
ANUMANTHA G. KANTHASAMY AND SIDDHARTH KAUL 411
25 Animal models of epilepsy
RICARDO M. ARIDA, ALEXANDRE V. SILVA, MARGARETH
R. PRIEL, AND ESPER A. CAVALHEIRO 438
26 Experimental models of hydrocephalus
OSAAMA H. KHAN AND MARC R. DEL BIGIO 457
27 Rodent models of experimental bacterial infections
in the CNS
TAMMY KIELIAN 472
28 Experimental models of motor neuron disease/amyotrophic
lateral sclerosis
R U T H D A N Z E I S E N , B I R G I T S C H W A L E N S T Ö C K E R ,
AND ALBERT C. LUDOLPH 487
 Contents vii

29 Animal models for sleep disorders

SEIJI NISHINO AND NOBUHIRO FUJIKI 504
30 Experimental models of muscle diseases
ANU SUOMALAINEN, KATJA E. PELTOLA MJOSUND, ANDERS
PAETAU, AND CARINA WALLGREN-PETTERSSON 544
Index 562
 Contributors

Ricardo M. Arida Esper A. Cavalheiro

Laboratory of Experimental Laboratory of Experimental
Neurology Neurology
Departments of Neurology and Departments of Neurology and
Neurosurgery Neurosurgery
Faculty of Medicine Faculty of Medicine
Federal University of São Paulo Federal University of São Paulo
Rvo Botucatu 862 Rvo Botucatu 862
04023 São Paulo 04023 São Paulo
Brazil Brazil

Joshua B. Bederson Pak H. Chan

Department of Neurosurgery Department of Neurosurgery and
Mount Sinai School of Medicine Neurosciences
1 Gustave L. Levy Place Stanford University Medical Center
Box 1136 Palo Alto, CA 93304
New York, NY 10029 USA
USA
Zhao Zhong Chong
Erica Butti Departments of Neurology and
Neuroimmunology Unit Anatomy and Cell Biology
San Raffaella Scientific Centers for Molecular Medicine and
Institute–DIBIT Institute for Environmental Health
Via Olgettina 58 Sciences
20132 Milano
Italy

viii
 List of contributors ix

Wayne State University School of Marc Fisher

Medicine Department of Neurology
8C-1 UHC University of Massachusetts Medical
4201 St. Antoine School
Detroit, MI 48201 UMASS/Memorial Health Care
USA 119 Belmont Street
Worcester, MA 01605
Shlomi Constantini USA
Department of Pediatric
Neurosurgery Rosemary A. Fricker-Gates
Dana Children’s Hospital School of Biosciences
Tel Aviv Medical Center Cardiff University
Tel Aviv 64239 Museum Avenue
Israel P.O. Box 911
Cardiff CF10 3US
Ruth Danzeisen UK
Department of Neurology
University of Ulm Nobuhiro Fujiki
Albert Einstein-Allee 11 (025) Center for Narcolepsy
89081 Ulm Stanford University School of
Germany Medicine
701B Welch Road
Marc R. Del Bigio Palo Alto, CA 93304
Department of Pathology USA
(Neuropathology)
University of Manitoba Roberto Furlan
D212 – 770 Bannatyne Avenue Neuroimmunology Unit
Winnipeg MB R3E 0W3 San Raffaele Scientific
Canada Institute–DIBIT
Via Olgettina 58
Stephen B. Dunnett 20132 Milan
School of Biosciences Italy
Cardiff University
Museum Avenue Monte A. Gates
P.O. Box 911 School of Biosciences
Cardiff CF10 3US Cardiff University
UK Museum Avenue
P.O. Box 911
Cardiff CF10 3US
UK
x List of contributors

Larry B. Goldstein Siddharth Kaul

Department of Neurology Department of Biomedical Sciences
Duke Center for Cerebrovascular 2062 Veterinary Medicine Building
Disease Iowa State University
Duke University Medical Center Ames, IA 50011
P.O. Box 3651 USA
Durham, NC 27710
USA Robert W. Kemp
AstraZeneca Inc.
Lilly Hsieh Alderley Park
Department of Neurosurgery and Macclesfield SK10 4TF
Neurological Sciences UK
Stanford University Medical School
1201 Welch Rd MSLS P357 Osaama H. Khan
Stanford, CA 94305 Department of Pathology
USA (Neuropathology)
University of Manitoba
Taichang Jang D212 – 770 Bannatyne Avenue
Department of Neurology and Winnipeg MB R3E 0W3
Clinical Neurosciences Canada
Stanford University Medical Center
Palo Alto, CA 93304 Tammy Kielian
USA Department of Neurobiology and
Developmental Sciences
Richard E. Jones University of Arkansas for Medical
Portland Veterans Affairs Medical Sciences College of Medicine
Center Room 110B Biomedical Research
Oregon Health and Science Center
University 4301 W. Markham St, Slot 510
R&D-31 Little Rock, AR 72205
3710 SW US Veterans Hospital Rd USA
Portland, OR 97239
Julia Kofler
USA
Department of Anesthesiology and
Anumantha G. Kanthasamy Peri-Operative Medicine
Department of Biomedical Sciences Oregon Health and Science
2062 Veterinary Medicine Building University
Iowa State University 3181 SW Sam Jackson Park Rd
Ames, IA 50011 Mail Code L335
USA Portland, OR 97239
USA
 List of contributors xi

Tarja Kohila Päivi Liesi

University of Helsinki Department of Biosciences
00014 Helsinki University of Helsinki
Finland P.O. Box 65
Viikinkaari 1
Ronen R. Leker 00014 Helsinki
Laboratory of Molecular Biology Finland
Bldg 36, Room 3c12
National Institute for Neurological Hans Link
Disorders and Stroke Department of Neurology
National Institutes of Health Karolinska Institute and Huddinge
Bethesda, MD 20892 University Hospital
USA M 98, 14186 Huddinge
Stockholm
Michael Lev Sweden
Department of Radiology
Harvard Medical School Jason M. Link
Boston, MA 02115 Portland Veterans Affairs Medical
USA Center
Oregon Health and Science
Faqi Li University
Departments of Neurology and R&D-31
Anatomy and Cell Biology 3710 SW US Veterans Hospital Rd
Centers for Molecular Medicine and Portland, OR 97239
Institute for Environmental Health USA
Sciences
Wayne State University School of Eng H. Lo
Medicine Departments of Neurology and
8C-1 UHC Radiology
4201 St. Antoine Harvard Medical School
Detroit, MI 48201 Boston, MA 02115
USA USA

Fuhai Li Albert C. Ludolph

Department of Neurology Department of Neurology
Duke University Medical Center University of Ulm
P.O. Box 3651 Oberer Eselsberg 45
Durham, NC 27710 89081 Ulm
USA Germany
xii List of contributors

Carolina M. Maier Seiji Nishino

Department of Neurosurgery and Center for Narcolepsy
Neurological Sciences Stanford University School of
Stanford University Medical School Medicine
1201 Welch Rd MSLS P357 701B Welch Rd, RM 142
Stanford, CA 94305 Palo Alto, CA 94304
USA USA

Kenneth Maiese Halina Offner

Departments of Neurology and Portland Veterans Affairs Medical
Anatomy and Cell Biology Center
Centers for Molecular Medicine and Oregon Health and Science
Institute for Environmental Health University
Sciences R&D-31
Wayne State University School of 3710 SW US Veterans Hospital Rd
Medicine Portland, OR 97239
8C-1 UHC USA
4201 St. Antoine
Detroit, MI 48201 Anders Paetau
USA Department of Pathology
Helsinki University Central Hospital
Gianvito Martino Haartmaninkatu 3
Neuroimmunology Unit 00290 Helsinki
San Raffaele Scientific Finland
Institute–DIBIT
Via Olgettina 58 Katja E. Peltola Mjosund
20132 Milano Programme of Neurosciences and
Italy Department of Neurology
University of Helsinki and Helsinki
Naoya Masutomi University
Toxicology Laboratory Central Hospital
Mitsubishi Pharma Corporation Biomedicum Helsinki
1-1-1 Kazusakamatari Haartmaninkatu 8
Kisarazu, Chiba 292-0818 00290 Helsinki
Japan Finland
 List of contributors xiii

Margareth R. Priel Fatima A. Sehba

Laboratory of Experimental Department of Neurosurgery
Neurology Mount Sinai School of Medicine
Departments of Neurology and 1 Gustave L. Levy Place
Neurosurgery Box 1136
Faculty of Medicine New York, NY 10029
Federal University of São Paulo USA
Rvo Botucatu 862
04023 São Paulo Makoto Shibutani
Brazil Division of Neuropathology
National Institute of Health Sciences
Lawrence Recht 1-18-1 Kamiyoga, Setagayu-ku
Department of Neurology and Tokyo 158-8501
Clinical Neurosciences Japan
University of Stanford Medical
School Alexandre V. Silva
Palo Alto, CA 93304 Laboratory of Experimental
USA Neurology
Departments of Neurology and
René Remie Neurosurgery
Department of Biomonitoring and Faculty of Medicine
Sensoring Federal University of São Paulo
University Center for Pharmacy Rvo Botucatu 862
Groningen University 04023 São Paulo
Antonius Deusinglaan 1 Brazil
9714 AW Groningen
The Netherlands Daniel Strbian
Department of Neurology
Birgitta Schwalenstöcker Helsinki University Central Hospital
Department of Neurology Haartmaninkatu 4
University of Ulm 00290 Helsinki
Albert Einstein-Allee 11 (025) Finland
89081 Ulm
Germany Anu Suomalainen
Department of Neurology
Helsinki University Central Hospital
Haartmaninkatu 4
00290 Helsinki
Finland
xiv List of contributors

Turgut Tatlisumak Carina Wallgren-Pettersson

Department of Neurology Department of Medical Genetics
Helsinki University Central Hospital University of Helsinki and
Haartmaninkatu 4 Folkhälsan Institute of Genetics
00290 Helsinki Haartmaninkatu 8
Finland 00290 Helsinki
Finland
George T. Taylor
Behavioral Neuroscience Group David Whittaker
University of Missouri – St. Louis Huntingdon Life Sciences Ltd
8001 Natural Bridge Rd. Woolley Road
St. Louis, MO 63121 Alconbury
USA Huntingdon PE28 4HS
UK
Eduardo M. Torres
School of Biosciences Juergen Weiss
Cardiff University Center for Biomedicine
Museum Avenue University of Heidelberg
P.O. Box 911 INF 347
Cardiff CF10 3US D-69120 Heidelberg
UK Germany

Richard J. Traystman Bao-Guo Xiao

Department of Anesthesiology and Department of Neurology
Peri-Operative Medicine Karolinska Institute and Huddinge
Oregon Health and Science University Hospital
University M 98, 14186 Huddinge
3181 SW Sam Jackson Park Rd Stockholm
Mail Code L335 Sweden
Portland, OR 97239
USA Frank Zimmermann
Center for Biomedicine
Arthur A. Vandenbark University of Heidelberg
Department of Neurology INF 347
Tykeson Multiple Sclerosis Research D-69120 Heidelberg
Laboratory Germany
Veterans Affairs Medical Center
Oregon Health and Science
University
Portland, OR 97239
USA
 Part I
Principles and general methods
 1
Introduction: Animal modeling – a precious tool
for developing remedies to neurological diseases
TURGUT TATLISUMAK AND MARC FISHER

Human beings owe a great deal to animals. From the earliest periods of history
of mankind, animals have been used by humans for food, clothing, tool
making, and for several other purposes. Primitive artists painted animal
figures onto stone surfaces; animal figures became parts of religions and tribal
identities. Over time, some animals were domesticated, serving as regular
sources of meat and milk; additionally, animals were used in farmwork and
for transport. Dogs were used to defend property and were trained for rescue
missions. Cats were used as pets as early as the ancient Egyptian Kingdom.
Interesting additional missions have been given to animals such as searching
for illicit drugs, explosives, and mushrooms. Some areas where we are still
strictly dependent on animals include the drug industry (e.g., insulin isolated
from swine pancreas), but there are also areas subject to intense debate (e.g.,
fur farming, fox hunting, and the cosmetics industry).
We are very much dependent on animals in medical research and in clinical
surgery training. Neurological diseases comprise a major health problem all
over the world and their importance continues to grow as the population ages
and as neurology moves from being largely a diagnostic field to one with more
therapeutic approaches. Neurological diseases already absorb approximately
one-fourth of health budgets in industrialized countries. It is urgent to develop
novel effective therapies for neurological diseases: the aging of the population
will increase the number of neurological patients whereas the labor force
available in the health sector appears to be decreasing. Additionally, the
burden of the neurological disease to the individual patient and their relatives
is more dramatic than diseases of other organs. Many critically important
discoveries regarding disease mechanisms and most therapies that are cur-
rently being used for neurological diseases have been developed in animal
models, and the need for animal models is expanding.
Use of animals for scientific purposes has a long history. One animal dies for
scientific reasons every second in the USA and every three seconds in the

Handbook of Experimental Neurology, ed. Turgut Tatlisumak and Marc Fisher. Published by Cambridge
University Press. # Cambridge University Press 2006.
4 Turgut Tatlisumak and Marc Fisher

European Union. Whereas total medical research has expanded several-fold

over recent decades, the number of animals used for scientific purposes has
remained the same or even slightly decreased in absolute terms, and substan-
tially decreased in relative terms. A Medline search with the word ‘‘rat’’ gave
1 100 000 hits and ‘‘mouse’’ gave 770 000 hits (March 2005). It is easy to
understand why the rat and the mouse are so popular in medical research.
They breed easily, profusely, and continuously, have a short gestational per-
iod, are relatively inexpensive, and can be housed in large numbers in relatively
small spaces; and their anatomy, physiology, biochemistry, genetical proper-
ties, and behavior are well described. Rats and mice are easy to handle and the
size of their organs is suitable for staining, antibody generation, and many
other research activities. Specimens from rats and mice can easily be stored
for later studies. Furthermore, the rat and mouse are not generally considered
as pets and their experimental use is more acceptable than other animals.
The ‘‘3 R’’ rule (Reduce, Refine, Replace) refers to the efforts to reduce the
number of animals used in scientific experiments, to plan and perform the
experiments in a way that decreases the suffering of animals, and to develop
alternative methods to replace the use of live animals. Even though the aim is
ethically well established, it is difficult to develop alternative approaches and
some are unreliable. Although the ethics of using animals in research is not a
new issue, standards remain to be established. It must be remembered that the
very early ethical principles regarding the use of animals in scientific research
were written with efforts initiated by scientists themselves in the 1830s, not by
animal activists. Furthermore, animal experimentation is rather expensive. If
alternative approaches were available, most researchers would readily aban-
don the use of animals. Interestingly, possessing a pet animal does not require
any training, while fishing or shooting animals does not require more than a
permit. Scientific use is strictly controlled, suitable facilities are required,
extensive training is a must, and permission must be obtained. Anyone can
take a pet animal to a veterinary physician for castration without permission of
regulatory authorities, despite the fact that this is not necessary for the ani-
mal’s health, alters its natural life course, and causes pain. To carry out a
similar procedure for scientific reasons would require regulatory approval.
The final target of animal experimenting is to develop remedies to cure human
diseases. Therefore, it is never unnecessary to mention the importance of
treating the experimental animals humanely as the source of scientific research
is humane and it must be accomplished in a humane way.
We felt frustrated with the difficulty of finding even the most fundamental
information in a centralized source for animal experimentation and to collect
information from a large number of articles some of which were published
 Introduction: Animal modeling 5

in journals that were difficult to access and was time-consuming. Therefore, we

decided to centralize the joint effort of over 60 universally well-recognized
scientists and cover most major issues about neurological animal methodology
under one cover. This is a first-of-its-kind book in its comprehensiveness. The
methods included in this book may improve animal welfare, decrease the
number of animals required, and may increase the quality of experiments.
Success in animal experiments and the reliability of the results largely depend
on the proper use of techniques including proper handling of the animals,
suitable anesthesia and analgesia, clean and least-damaging surgery, and use
of most appropriate models and techniques. Failure in following the crucial
steps in animal experimenting will lead to unreliable results and unnecessary
suffering of animals and sometimes of the researcher when he/she is bitten.
This book comprises 30 chapters and is divided into two parts. The first part
of this book deals with general principles and methodology, whereas the
second part delivers comprehensive data on animal models of individual
neurological disorders. In each disease chapter, the authors first discuss the
magnitude of the problem in epidemiologic and economic dimensions fol-
lowed by detailed and critical information on present models. References are
generally limited and readers who are interested in more in-depth knowledge
are encouraged to further explore the references listed in each chapter or
directly contact experts in that field. This book is planned to deliver a broad
view to young neuroscientists, but may even be useful to more experienced
scientists. Animal modeling deals mostly with rodents and with other animal
species where appropriate.
We are grateful to all the authors for their contributions and the time spent
in preparing them. Even though we engendered our best to cover all major
neurological experimental issues in this book, space limitations led to com-
promises. We hope that scientists will benefit from this book. Feedback from
readers is most welcome. It is of our mutual interest that, in the long run, these
animal models can be replaced with novel technologies that are at the same
time ethically more acceptable and scientifically more reliable, making new
editions of this book unnecessary.
 2
Ethical issues, welfare laws, and regulations
DAVID WHITTAKER

2.1 Introduction
The ethics, morals, and laws of any culture or nation are intimately interwoven
and dependent upon each other for their continuation within that society. At
the same time most cultures are under continual evolution, change, and
development due to many factors, but usually due to ingress, influences, and
pressures from other external factors and cultures. This is best illustrated by
the notion that ‘‘developed’’ nations frequently bring about cultural changes in
very old ‘‘traditional societies’’ through their presence and financial impact.
Once there is cultural change, then almost certainly it will be followed by
changes in the ethical and moral stances taken. Ultimately the laws and
regulations will no longer reflect or uphold the current ‘‘values’’ of that society
and will need modification.
This point is made to emphasize the fact that ethics and morals are not only
diverse in a global sense but also dynamic. What was once ethically acceptable
in history (e.g., slavery) may now be locally or globally seen as morally wrong
and laws enacted to reflect those views.
With regard to laws it must also be acknowledged that as the ‘‘global village’’
becomes an increasing reality so does a meeting of minds on points of ethics
and morals. As the meeting of minds becomes a reality, then it is possible to
develop and implement international laws and regulations. This is particularly
pertinent when considering the European position with regard to the Council
of Europe (CoE) and the European Union (EU).
Finally in this introduction it must be emphasized that the roots of ethics
and moral principles lie in the considerations and writings of the great philo-
sophers. It is not the intention of this paper to concentrate on the history and
theories which consider the rights and wrongs of animal experimentation.
However, consideration will be given to the more practical and pragmatic
ethical considerations surrounding animal use.

Handbook of Experimental Neurology, ed. Turgut Tatlisumak and Marc Fisher. Published by Cambridge
University Press. # Cambridge University Press 2006.
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