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T E C H N I Q U E S IN T H E B E H A V I O R A L A N D N E U R A L S C I E N C E S

V O L U M E 15

HANDBOOK OF STRESS AND THE BRAIN

Part 1" The Neurobiology of Stress

Previously published in TECHNIQUES IN THE BEHAVIORAL AND NEURAL SCIENCES

Volume 1: Feeding and Drinking, by F. Toates and N.E. Rowland (Eds.), 1987, ISBN 0-444-80895-7
Volume 2: Distribution-free Statistics: Application-oriented Approach, by J. Krauth, 1988,
ISBN 0-444-80934-1, Paperback ISBN 0-444-80988-0
Volume 3: Molecular Neuroanatomy, by F.W. Van Leeuwen, R.M. Buijs, C.W. Pool and O. Pach (Eds.),
1989, ISBN 0-444-81014-5, Paperback ISBN 0-444-81016-1
Volume 4: Manual of Microsurgery on the Laboratory Rat, Part 1, by J.J. van Dongen, R. Remie,
J.W. Rensema and G.H.J. van Wunnik (Eds.), 1990, ISBN 0-444-81138-9, Paperback
ISBN 0-444-81139-7
Volume 5: Digital Biosignal Processing, by R. Weitkunat (Ed.), 1991, ISBN 0-444-81140-0, Paperback
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Volume 6: Experimental Analysis of Behavior, by I.H. Iversen and K.A. Lattal (Eds.), 1991, Part 1,
ISBN 0-444-81251-2, Paperback ISBN 0-444-89160-9, Part 2, ISBN 0-444-89194-3, Paperback
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ISBN 0-444-81194-X, Paperback ISBN 0-444-89375-X
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and R.E. Wimer (Eds.), 1992, ISBN 0-444-81249-0, Paperback ISBN 0-444-89682-1
Volume 9: Research Designs and Methods in Psychiatry, by M. Fava and J.F. Rosenbaum (Eds.), 1992,
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J. Krauth (Ed.), 2000, ISBN 0-444-50637-3, Paperback ISBN 0-444-50638-1

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 T E C H N I Q U E S IN THE B E H A V I O R A L A N D N E U R A L SCIENCES

Series Editor

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Dtisseldorf

V O L U M E 15

H A N D B O O K OF STRESS A N D THE B R A I N
Part l" The Neurobiology of Stress

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T. S T E C K L E R
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 List of Contributors, Part 1

K.-B. Abel, Division of Endocrinology, Children's Hospital Boston, Harvard Medical

School, 300 Longwood Avenue, Boston, MA 02115, USA
D. Adams, Laboratory of Molecular Psychiatry, Departments of Psychiatry and
Pharmacology, Yale University School of Medicine, 34 Park Street, New Haven,
CT 06508, USA
L Akirav, Department of Psychology and, The Brain and Behavior Research Center,
University of Haifa, Haifa 31905, Israel
O.F.X. Almeida, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, D-80804
Munich, Germany
B. Bali, Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine,
Hungarian Academy of Science, Szigony u. 43, Budapest H-1083, Hungary
C.W. Berridge, Departments of Psychology and Psychiatry, University of Wisconsin, 1202
W. Johnson Street, Madison, WI 53706, USA
J.J. Cerqueira, Life and Health Science Research Institute, Health Science School,
University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
K.C. Chambers, Department of Psychology, University of Southern California, Seely G.
Mudd Bldg. # 501, Los Angeles, CA 90089-1061, USA
G.P. Chrousos, Pediatric and Reproductive Endocrinology Branch, National Institute of
Child Health and Human Development, National Institutes of Health, Building 10 Room
9D42, 10 Center Drive MSC 1583, Bethesda, MD 20892-1583, USA
O. Cohen, Departments of Biological Chemistry and Psychology, The Hebrew University of
Jerusalem, Jerusalem, Israel
W.E. Cullinan, Department of Biomedical Sciences, Marquette University, Milwaukee,
WI 53233, USA
B. CzOh, Clinical Neurobiology Laboratory, German Primate Center, Kellnerweg 4, 37077
Gottingen, Germany
F.M. Dautzenberg, Johnson & Johnson Pharmaceutical Research & Development,
A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium
E.R. De Kloet, Division of Medical Pharmacology, LACDS-LUMC, University of Leiden,
P.O. Box 9502, 2300 RA Leiden, The Netherlands
A.J. Douglas, Section of Biomedical Sciences, DBCLS, University of Edinburgh, Hugh
Robson Building, George Square, Edinburgh EH8 9XD, UK
G. Drolet, Centre de Recherche en Neurosciences, CHUL, RC-9800, 2705 Boulevard
Laurier, Ste-Foy G1V 4G2 QC, Canada
S.K. Droste, Henry Wellcome Laboratories for Integrative Neuroscience and
Endocrinology, The Dorothy Hodgkin Building, University of Bristol, Whitson Street,
Bristol, BS1 3NY, UK
J. Du, Laboratory of Molecular Pathophysiology, National Institute of Mental Health,
Building 49, Room B1EE16, 49 Convent Drive, Bethesda, MD 20892-4405, USA
vi

R.S. Duman, Laboratory of Molecular Psychiatry, Departments of Psychiatry and

Pharmacology, Yale University School of Medicine, 34 Park Street, New Haven,
CT 06508, USA
Y. Dwivedi, Psychiatric Institute, Department of Psychiatry, University of Illinois at
Chicago, 1601 W. Taylor St, Chicago, IL 60612, USA
W.C. Engeland, Departments of Surgery and Neuroscience, University of Minnesota, Mayo
Mail Code 120, 420 Delaware St SE, Minneapolis, MN 55455, USA
N. Farzad, Laboratory of Molecular Pathophysiology, National Institute of Mental
Health, Building 49, Room B1EE16, 49 Convent Drive, Bethesda, MD 20892-4405,
USA
H. Figueiredo, Department of Psychiatry, University of Cincinnati, 231 Albert Sabin Way,
Cincinnati, OH 45267-0559, USA
E. Fuchs, Clinical Neurobiology Laboratory, German Primate Center, Kellnerweg 4, 37077
Gottingen, Germany
A.J. Fulford, Department of Anatomy, University of Bristol, Southwell Street, Bristol,
BS2 8EJ, UK
D. Glick, Department of Biological Chemistry, The Hebrew University of Jerusalem,
Jerusalem, Israel
E. Gould, Department of Psychology, Princeton University, Princeton, NJ 08544, USA
T.D. Gould, Laboratory of Molecular Pathophysiology, National Institute of Mental
Health, Building 49, Room B 1EEl 6, 49 Convent Drive, Bethesda, MD 20892-4405, USA
A. Gratton, McGill University, Douglas Hospital Research Center, Montreal, H4H 1R3 QC,
Canada
N.A. Gray, Laboratory of Molecular Pathophysiology, National Institute of Mental Health,
Building 49, Room B1EE16, 49 Convent Drive, Bethesda, MD 20892-4405, USA
M.S. Harbuz, University Research Centre for Neuroendocrinology, Bristol Royal Infirmary,
Marlborough Street, Bristol, BS2 8HW, UK
U.L. Hayes, University of Massachusetts, Amherst, MA, USA
A.L.O. Hebb, Department of Pharmacology, Faculty of Medicine, Dalhousie University,
Sir Charles Tupper Medical Building, 5850 College Street, Halifax, NS B3H 1X5,
Canada
S.C. Heinrichs, Boston College, Department of Psychology, McGuinn Hall, 140
Commonwealth Avenue, Chestnut Hill, MA 02467, USA
J.P. Herman, Department of Psychiatry, University of Cincinnati, 231 Albert Sabin Way,
Cincinnati, OH 45267-0559, USA
M.C. Holmes, Endocrinology Unit, Molecular Medicine Centre, Edinburgh University,
Western General Hospital, Edinburgh EH4 2XU, UK
S. Y.T. Hsu, Department of Obstetrics and Gynecology, Division of Reproductive Biology,
Stanford University School of Medicine, Pasteur Drive, Room A344E, Stanford,
CA 94305-5317, USA
C.D. Ingram, Psychobiology Research Group, School of Neurology, Neurobiology
and Psychiatry, University of Newcastle, Royal Victoria Infirmary, Newcastle NE1
4LP, UK
M. Joels, Swammerdam Institute for Life Sciences, Section Neurobiology, University of
Amsterdam, Kruislaan 320, 1098 SM Amsterdam, The Netherlands
N.H. Kalin, Department of Psychiatry and Psychology, University of Wisconsin, 6001
Research Park Blvd., Madison, WI 53719, USA
 vii

A.M. Karssen, Department of Psychiatry and Behavioral Sciences, School of Medicine,

Stanford University, MSL5, P124, 1201 Welch Road, Palo Alto, CA 94304-5485, USA
T. Kino, Pediatric and Reproductive Endocrinology Branch, National Institute of Child
Health and Human Development, National Institutes of Health, Building 10 Room
9D42, 10 Center Drive MSC 1583, Bethesda, MD 20892-1583, USA
G.F. Koob, Department of Neuropharmacology, The Scripps Research Institute, La Jolla,
CA 92037, USA
K.J. Kovdcs, Laboratory of Molecular Neuroendocrinology, Institute of Experimental
Medicine, Hungarian Academy of Science, Szigony u. 43, Budapest H-1083, Hungary
H.J. Krugers, Swammerdam Institute for Life Sciences, Section Neurobiology, University of
Amsterdam, Kruislaan 320, 1098 SM Amsterdam, The Netherlands
S. Laforest, Centre de Recherche en Neurosciences, CHUL, RC-9800, 2705 Boulevard
Laurier, Ste-Foy G1V 4G2 QC, Canada
M. Le Moal, INSERM U588, Institut Fran~;ois Magendie, 1 rue Camille St Saans, 33077
Bordeaux, France
V. Lemaire, INSERM U588, Institut Francois Magendie, 1 rue Camille St Sa6ns, 33077
Bordeaux, France
S. Levine, Department of Psychiatry, Center for Neuroscience, University of California at
Davis, Davis, CA 95616, USA
A.C.E. Linthorst, Henry Wellcome Laboratories for Integrative Neuroscience and
Endocrinology, University of Bristol, The Dorothy Hodgkin Building, Whitson Street,
Bristol BS1 3NY, UK
J. Lu, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, D-80804 Munich,
Germany
S.J. Lupien, Laboratory of Human Psychoneuroendocrine Research, Douglas Hospital
Research Center, 6875 Bldg. Lasalle, Verdun, H4H-1RS QC, Canada
F.S. Maheu, Department of Psychology, University of Montreal, 6875 Bld Lasalle,
Montreal, H4H 1R3 QC, Canada
J.A. Majzoub, Division of Endocrinology, Children's Hospital Boston, Harvard Medical
School, 300 Longwood Avenue, Boston, MA 02115, USA
H.K. Manji, Laboratory of Molecular Pathophysiology, National Institute of Mental
Health, Building 49, Room B 1EEl 6, 49 Convent Drive, Bethesda, MD 20892-4405, USA
C.A. Marsden, School of Biomedical Sciences, Institute of Neuroscience, University of
Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK
O.C. Meijer, Division of Medical Pharmacology/LACDR-LUMC, Leiden/Amsterdam
Center for Drug Research, Leiden University Medical Center, P.O. Box 9502, 2300 RA
Leiden, The Netherlands
I.H. Mikl6s, Laboratory of Molecular Neuroendocrinology, Institute of Experimental
Medicine, Hungarian Academy of Science, Szigony u. 43, Budapest H-1083, Hungary
N.K. Mueller, Department of Psychiatry, University of Cincinnati, 231 Albert Sabin Way,
Cincinnati, OH 45267-0559, USA
Z. NOmethy, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, D-80804 Munich,
Germany
M. P(tez-Pereda, Department of Endocrinology, Max Planck Institute of Psychiatry,
Kraepelinstr 10, 80804 Munich, Germany
G.N. Pandey, Department of Psychiatry, Psychiatric Institute, University of Illinois at
Chicago, 1601 W. Taylor St, Chicago, IL 60612, USA
viii

J.M. Pego, Life and Health Science Research Institute, Health Science School, University of
Minho, Campus de Gualtar, 4710-057 Braga, Portugal
J.D. Peters, Department of Psychology, Princeton University, Princeton, NJ 08544, USA
P.V. Piazza, INSERM U-588, Universit6 de Bordeaux 2, Institut Frangois Magendie, 1 Rue
Camille Saint-Satins, 33077 Bordeaux Cedex, France
J. Prickaerts, Johnson & Johnson Pharmaceutical Research & Development, a Division of
Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
J.M.H.M. Reul, Henry Wellcome Laboratories for Integrative Neuroscience and
Endocrinology, The Dorothy Hodgkin Building, University of Bristol, Whitson Street,
Bristol, BS1 3NY, UK
G. Richter-Levin, Department of Psychology, The Brain and Behavior Research Center,
University of Haifa, Haifa 31905, Israel
M.A. Riva, Department of Pharmacological Sciences, Center for Neuropharmacology,
University of Milan, Via Balzaretti 9, 20133 Milan, Italy
P.H. Roseboom, Department of Psychiatry and Pharmacology, 6001 Research Park Blvd.,
Madison, WI 53719, USA
R. Rupprecht, Department of Psychiatry, Nussbaumstr. 7, 80336 Munich, Germany
M. Schmidt, Division of Medical Pharmacology/LACDR-LUMC, University of Leiden,
P.O. Box 9502, 2300 RA Leiden, The Netherlands
J.R. Seckl, Endocrinology Unit, Molecular Medicine Centre, Edinburgh University,
Western General Hospital, Edinburgh EH4 2XU, UK
B.B. Simen, Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharma-
cology, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA
H. Soreq, Department of Biological Chemistry, The Hebrew University of Jerusalem,
Jerusalem, Israel
N. Sousa, Life and Health Science Research Institute, Health Science School, University of
Minho, Campus de Gualtar, 4710-057 Braga, Portugal
G.K. Stalla, Department of Endocrinology, Max Planck Institute of Psychiatry,
Kraepelinstr. 10, 80804 Munich, Germany
S. Stanford, Department of Pharmacology, University College London, Gower Street,
London WC1E 6BT, UK
T. Steckler, Johnson & Johnson Pharmaceutical Research & Development, A Division of
Janssen Pharmaceutica N.V., Turnhoutseweg 30, 2340 Beerse, Belgium
R.M. Sullivan, Centre de Recherche Fernand-S6guin, Universit6 de Montr6al, Montreal,
H4H 1R3 QC, Canada
Y.M. Ulrich-Lai, Department of Psychiatry, Albert Sabin Way, University of Cincinnati,
Cincinnati, OH 45267-0559, USA
R.J. Valentino, The Children's Hospital of Philadelphia, 402C Abramson Pediatric Research
Center, 34th and Civic Center Blvd, Philadelphia, PA 19104, USA
E.J. Van Bockstaele, Department of Pathology, Anatomy and Cell Biology, Thomas
Jefferson University, 1020 Locust St, Philadelphia, PA 19107, USA
J.M. Verkuyl, Swammerdam Institute for Life Sciences, Section Neurobiology, University of
Amsterdam, Kruislaan 320, 1098 SM Amsterdam, The Netherlands
N. Weekes, Department of Psychology, Pomona College, 550 N. Harvard Avenue,
Claremont, CA 91711, USA
J.L.W. Yau, Endocrinology Unit, Molecular Medicine Centre, Edinburgh University,
Western General Hospital, Edinburgh EH4 2XU, UK
R. Yirmiya, Department of Psychology, The Hebrew University of Jerusalem, Jerusalem,
Israel
P.-X. Yuan, Laboratory of Molecular Pathophysiology, National Institute of Mental
Health, Building 49, Room B 1EEl 6, 49 Convent Drive, Bethesda, MD 20892-4405, USA
R. Zhou, Laboratory of Molecular Pathophysiology, National Institute of Mental Health,
Building 49, Room B1EE16, 49 Convent Drive, Bethesda, MD 20892-4405, USA
E.P. Zorrilla, Department of Neuropharmacology, The Scripps Research Institute,
CVN-7, La Jolla, CA 92037, USA
This Page Intentionally Left Blank
 Preface

Stress is a phenomenon being all around us, but seemingly being too well known and too
little understood at the same time, despite the fact that the field has advanced enormously
over recent years. We have learned that stress can shape various types of behaviour in
the individual long after exposure to the stressor itself has terminated. Exposure to a
stressful stimulus during the perinatal period, for example, can have long-term consequences
over weeks and months, well into adulthood. This is accompanied by a variety of
characteristic neurochemical, endocrine and anatomical changes in the brain, leading,
for example, to changes in neural plasticity and cognitive function, motivation and
emotionality.
We have started to discover the differentiated effects of various stressors in the brain and
how expression of a wide variety of gene products will be altered in the CNS as a function
of the type and duration of the stressor. Activity in higher brain areas in turn will shape the
response to acute and chronic stress and there are intricate interactions with, for example,
immune functions. Cytokines will access the brain and affect its function at various levels.
It has become increasingly clear that stress serves as one of the main triggers for
psychiatric and non-psychiatric disorders, including depression, anxiety, psychosis,
drug abuse and dementia. Recognizing these intricate relationships has initiated a wealth
of research into the development of novel animal models and novel treatment strategies
aiming at influencing stress responsivity in patients suffering from these diseases.
Moreover, novel technologies, such as molecular techniques, including gene targeting
methods and D N A microarray methods start to unravel the cellular events taking place as a
consequence of stress and facilitate the understanding of how stress affects the brain.
Thus, the topic of stress, the brain and behaviour gains increasing relevance, both from a
basic scientific and clinical perspective, and spans a wide field of expertise, ranging from
the molecular approach to in-depth behavioural testing and clinical investigation. This book
aims at bringing these disciplines together to provide an update of the field and an outlook
to the future. We think these are exciting times in a rapidly developing area of science
and hope that the reader will find it both useful as an introductory text as well as a detailed
reference book. The Handbook of Stress and the Brain is presented in two parts, i.e. Part 1:
The Neurobiology of Stress, and Part 2: Stress: Integrative and Clinical Aspects.
This part, Part 1, addresses basic aspects of the neurobiology of the stress response
including the involvement of neuropeptide, neuroendocrine and neurotransmitter systems,
and its corollaries regarding gene expression and behavioural processes such as cognition,
motivation and emotionality.

Thomas Steckler
Ned Kalin
Hans Reul

xi
A Memorial for David de Wied (1925-2004)

It is almost an eerie coincidence that this volume, dedicated to the subjects of Stress and
Behavior, should be published at a time when the field has lost one of its giants and the man
whose work has inspired much of what is written here. On February 21, 2004 Professor
David de Wied died. David had just celebrated his 79th birthday. For me not only did the
field lose one of its founding fathers but I lost a dear friend. Professor de Wied was born on
January 12, 1925. His life prior to embarking on his professional career was marked by
a period of several years when he went underground and was in hiding during the German
occupation of Holland. Following the war he decided to attend the University of Groningen
to study medicine. This involved a tremendous effort since he had lost many precious
academic years. He did receive his medical degree in 1955. I shall not document the details of
his remarkable academic achievements. These are presented in detail in a volume dedicated
to David on his 75th birthday (Smelik and Witter, 2000) and more recently by de Kloet
(2004). In my chapter on the history of stress research I devoted several pages to David de
Wied and his importance to the field, but his impact on the field was of such significance that
it is worth repeating.
David was in every sense a pioneer and a visionary. I have often wondered how one
defines a visionary. Perhaps the critical dimension is the ability to see relationships between
events that are not immediately apparent to normal mortals. He is best known for his
formulation of the "neuropeptide concept" although throughout his career he made many
other major contributions. In its simplicity the neuropeptide concept postulated that there
were peptides produced in the brain and pituitary that directly influenced brain function,
and of particular importance, behavior. The field of hormones and behavior at the time
when David began to work on the effects of peptides on behavior was almost exclusively
dedicated to studying the effects of gonadal steroids on sexual behavior. There were a few
scattered reports of effects of thyroid and adrenal steroid compounds but they had little
impact. The demonstration that neuropeptides could influence complex behavioral processes
such as learning and memory was indeed revolutionary and met with a great deal of
skepticism when first introduced. However, the skeptics were silenced when he continued
to demonstrate the powerful influence of these molecules on behavior. It was primarily
based on this work that fundamental behavioral processes were integrated into the general
rubric of neuroendocrinology and new dimensions of the effects of the hormones of the
hypothalamic-pituitary-adrenal axis on behavior were introduced. The neuropeptide
concept pre-dated the characterization of the "releasing hormones" synthesized in the
hypothalamus. That these hormones have been shown to have a profound influence on
behavior is one of the legacies of David's work.
In 1963 he became Professor of Medical Pharmacology at the University of Utrecht
which in 1968 became the Rudolf Magnus Institute of Pharmacology in honor of the Dutch
pharmacologist Rudolf Magnus. This institute rapidly became the Mecca for the study
of hormones and behavior. It was the place to visit and study if your field of interest

xiii
xiv

encompassed neuroendocrinology and behavior. Investigators came from every part of the
world to study at the institute. On the numerous occasions that I lectured in the institute
I was always prepared to be challenged by David and his students. The discussions were
vigorous, animated and sometimes heated, but always stimulating and provocative.
David's legacy extends well beyond his scientific contributions. There are multitudes of
Ph.D. and post-doctoral students as well as collaborators who are indebted to him. They
were privileged to share his scientific rigor, and perhaps of more importance, his unique
intellect. On the occasion of his 75th birthday celebrations the room was filled with many of
these students and colleagues. What was impressive is that many of them are now the current
leaders in the field.
Although he is best known for his life as a scientist there was much more to the man. He
had other passions that made up his life. He was an avid art collector and loved music. Until
his death he continued to play the violin and take music lessons. We shared a common love
for both music and art. One of our secret ambitions was to perform the famous tenor and
baritone duet from Bizet's "The Pearl Fisher." There were two problems, first neither of
us could qualify as a tenor and second we really did not sing very well. This did not prevent
us from singing opera at any occasion whether it be a dinner at a congress or a party in
Hungary.
David was a complex man. He received numerous prestigious honors throughout his
career and yet in his later years he did not feel he had achieved the recognition he deserved.
Perhaps the problem with being the originator of a concept that gains universal acceptance
is that its origin is often forgotten. David had the most unusual sense of humor I have
encountered. On one occasion my youngest daughter spent a weekend with us and David
and his wife Lie on the Italian Riviera. She spent the first day terrified of him until she
realized that he was indeed one of the funniest people she had ever met. She spent the next
few days in almost constant laughter.
It was my dream and hope that David and I would have a grand celebration for our
joint 80th birthdays in 2005. We were both overjoyed when we experienced the millennium.
That dream has now been shattered. I will continue to revere and respect him for all the
contributions he has made to biology and to the quality of all our lives. We shared many
adventures, many avid scientific discussions and the pleasure of watching the growth of our
science. These memories are always present and it was indeed a privilege to have shared
these with him over many years.

Seymour Levine
Center for Neuroscience
University of California, Davis

References
De Kloet, E.R. (2004) In honour of David de Wied. Psychoneuroendocrinology
(in press).
Smelik, P.G. and Witter, A. (2000) David de Wied a biographical sketch. In: David
de Wied (Honorary Editor), Neuropeptides, Basics and Perpectives. Elsevier,
Amsterdam.
 Contents, Part 1

List of Contributors, Part 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Preface ...................................................... xi

A Memorial for David de Wied (1925-2004) . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii

Section 1. Concepts of Stress

1.1. Stress: an historical perspective

S. Levine (Davis, CA, USA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.2. The neuropsychology of stress

T. Steckler (Beerse, Belgium) ............................ 25

1.3. An introduction to the HPA axis

A.J. Fulford and M.S. Harbuz (Bristol, UK) . . . . . . . . . . . . . . . . . 43

1.4. Hormones of the pituitary

M. Pfiez-Pereda and G.K. Stalla (Munich, Germany) . . . . . . . . . . . 67

1.5. Molecular biology of the HPA axis

K.-B. Abel and J.A. Majzoub (Boston, MA, USA) ............ 79

1.6. The hypothalamic-pituitary-adrenal axis as a dynamically organized system:

lessons from exercising mice
J.M.H.M. Reul and S.K. Droste (Bristol, UK) . . . . . . . . . . . . . . . . 95

Section 2. Hypothalamic Hormones Involved in Stress Responsivity

2.1. Novel C R F family peptides and their receptors: an evolutionary analysis

S.Y.T. Hsu (Stanford, CA, USA) . . . . . . . . . . . . . . . . . . . . . . . . . 115

2.2. Molecular regulation of the C R F system

P.H. Roseboom, N.H. Kalin, T. Steckler and F.M. Dautzenberg
(Madison, WI, USA and Beerse, Belgium) . . . . . . . . . . . . . . . . . . . 133

2.3. Behavioral consequences of altered corticotropin-releasing factor activation in

brain: a functionalist view of affective neuroscience
S.C. Heinrichs (Chestnut Hill, MA, USA) . . . . . . . . . . . . . . . . . . . 155

XV
xvi

2.4. The roles of urocortins 1, 2, and 3 in the brain

E.P. Zorrilla and G.F. Koob (La Jolla, CA, USA) . . . . . . . . . . . . . 179

2.5. Vasopressin and oxytocin

A.J. Douglas (Edinburgh, UK) . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

2.6. The role of vasopressin in behaviors associated with aversive stimuli

K.C. Chambers and U.L. Hayes (Los Angeles, CA and Amherst, MA,
USA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

Section 3. Stress and the HPA Axis

3.1. Corticosteroid receptors and HPA-axis regulation

E.R. de Kloet, M. Schmidt and O.C. Meijer (Leiden, The Netherlands) 265

3.2. Glucocorticoid effects on gene expression

T. Kino and G.P. Chrousos (Bethesda, MD, USA) ............ 295

3.3. The role of 11 [3-hydroxysteroid dehydrogenases in the regulation of

corticosteroid activity in the brain
J.R. Seckl, J.L.W. Yau and M.C. Holmes (Edinburgh, UK) . . . . . . 313

3.4. Corticosteroids and the blood-brain barrier

A.M. Karssen, O.C. Meijer and E.R. de Kloet (Leiden,
The Netherlands) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329

3.5. Glucocorticoids and motivated behaviour

V. Lemaire, P.V. Piazza and M. Le Moal (Bordeaux, France) . . . . . 341

3.6. Effects of glucocorticoids on emotion and cognitive processes in animals

J. Prickaerts and T. Steckler (Beerse, Belgium) . . . . . . . . . . . . . . . . 359

3.7. Glucocorticoids: effects on human cognition

S.J. Lupien, F.S. Maheu and N. Weekes (Montreal, QC, Canada and
Claremont, CA, USA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

Section 4. Neurotransmitter Systems Involved in Stress Responsivity

4.1. Neurocircuit regulation of the hypothalamo-pituitary-adrenocortical stress

response- an overview
J.P. Herman, N.K. Mueller, H. Figueiredo and W.E. Cullinan
(Cincinnati, OH and Milwaukee, WI, USA) . . . . . . . . . . . . . . . . . . 405

4.2. Sympatho-adrenal activity and hypothalamic-pituitary-adrenal axis regulation

Y.M. Ulrich-Lai and W.C. Engeland (Minneapolis, MN, USA) . . . . 419

4.3. The locus coeruleus-noradrenergic system and stress: modulation of arousal

state and state-dependent behavioral processes
C.W. Berridge (Madison, WI, USA) . . . . . . . . . . . . . . . . . . . . . . . 437
 xvii

4.4. Functional interactions between stress neuromediators and the locus

coeruleus-norepinephrine system
R.J. Valentino and E.J. Van Bockstaele (Philadelphia, PA, USA) 465

4.5. Regional specialisation in the central noradrenergic response to unconditioned

and conditioned environmental stimuli
S.C. Stanford and C.A. Marsden (London, UK and Nottingham, UK) 487

4.6. Stress, corticotropin-releasing factor and serotonergic neurotransmission

A.C.E. Linthorst (Bristol, UK) . . . . . . . . . . . . . . . . . . . . . . . . . . . 503

4.7. Modulation of glutamatergic and GABAergic neurotransmission by

corticosteroid hormones and stress
M. Joels, H.J. Krugers and J.M. Verkuyl
(Amsterdam, The Netherlands) . . . . . . . . . . . . . . . . . . . . . . . . . . . 525

4.8. Neuroactive steroids

R. Rupprecht (Munich, Germany) ........................ 545

4.9. Endogenous opioids, stress, and psychopathology

A.L.O. Hebb, S. Laforest and G. Drolet (Ste-Foy, QC, Canada) . . . 561

4.10. Acetylcholinesterase as a window onto stress responses

H. Soreq, R. Yirmiya, O. Cohen and D. Glick (Jerusalem, Israel) .. 585

4.11. Pathways and transmitter interactions mediating an integrated stress response

C.D. Ingram (Newcastle, UK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609

Section 5. Neuroplasticity and Stress

5.1. The intracellular signaling cascade and stress

Y. Dwivedi and G.N. Pandey (Chicago, IL, USA) . . . . . . . . . . . . . 643

5.2. The role of neurotrophic factors in the stress response

M.A. Riva (Milan, Italy) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665

5.3. Transcription factors as modulators of stress responsivity

R.S. Duman, D.H. Adams and B.B. Simen (New Haven, CT, USA) 679

5.4. Experience, structural plasticity and neurogenesis

J.D. Peters and E. Gould (Princeton, NJ, USA) . . . . . . . . . . . . . . . 699

5.5. Adult neurogenesis in rodents and primates: functional implications

E. Fuchs and B. Cz6h (G6ttingen, Germany) . . . . . . . . . . . . . . . . . 711

5.6. Cellular and molecular analysis of stress-induced neurodegeneration - metho-

dological considerations
J. Lu, Z. N~methy, J.M. Pego, J.J. Cerqueira, N. Sousa and O.F.X.
Almeida (Munich, Germany and Braga, Portugal) . . . . . . . . . . . . . . 729
xviii

5.7. Enhancing resilience to stress: the role of signaling cascades

P.-X. Yuan, R. Zhou, N. Farzad, T.D. Gould,
N.A. Gray, J. Du and H.K. Manji (Bethesda, MD, USA) ....... 751

Section 6. The Stressed Brain

6.1. Psychological and physiological stressors

K.J. Kovfics, I.H. Mikl6s and B. Bali (Budapest, Hungary) . . . . . . . 775

6.2. Involvement of the amygdala in the neuroendocrine and behavioral

consequences of stress
I. Akirav and G. Richter-Levin (Haifa, Israel) . . . . . . . . . . . . . . . . 793

6.3. Role of prefrontal cortex in stress responsivity

A. Gratton and R.M. Sullivan (Montreal, QC, Canada) . . . . . . . . . 807

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819

 SECTION 1

Concepts of Stress
This Page Intentionally Left Blank
T. Steckler, N.H. Kalin and J.M.H.M. Reul (Eds.)
Handbook of Stress and the Brain, Vol. 15
ISBN 0-444-51173-3
Copyright 2005 Elsevier B.V. All rights reserved
CHAPTER 1.1

Stress" an historical perspective

Seymour Levine

Department of Psychiatry, Center for Neuroscience, University of California, Davis, California 95616, USA

Abstract: Some of the major landmarks in the history of neuroendocrinology, glucocorticoid physiology and
psychoneuroendocrinology are discussed in this chapter. The primary emphasis is on the evolution of the major theories
and their experimental underpinnings on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Initially an
attempt was made to deal with the issues concerning the definitions of stress. The origins of the stress concept, the
neural control of the pituitary, the history of the search for corticotrophin-releasing factor (CRF), and the
developments that resulted in shaping the current views of the action of the adrenal hormones are elaborated. Further,
the role of environment and behavior on the regulation of the HPA axis and the effects of specific neuropeptides on
behavior were also covered. The purpose of this chapter is to provide a perspective on the major events that were crucial
in the history of stress research that shaped the directions of the field.

"The past is never dead. It's not even the past"

William Faulkner

Introduction books dedicated to this subject. What is also evident

from the information obtained from the computer
During the course of my career, which now spans over is that the number of publications is accelerating.
five decades, I could not begin to count the number Over 60,000 papers have been published since the
of conferences, workshops, and symposia related to beginning of the new millennium. A close examina-
stress that I have attended. I will not attempt to tion of only a small sample of these references made it
describe the number of times during these meeting abundantly clear that the term stress was used in
that at least one, if not several, of the participants had so many different ways that it would be necessary to
championed the notion that we discard the concept determine, for each article listed, the precise manner
for a more precise definition. The absolute failure of the term was used and in what context. It would be
these attempts is attested to by my most recent visit further difficult to specify all the different disciplines
to one of my favorite biomedical computer searches. that have in some way found the concept of stress
As of this moment Pub-Med listed 209,744 references useful, though each discipline will define stress in its
that in one way or another had some reference to the own idiosyncratic manner.
term stress. It would be difficult to predict what this
number will be at the time this chapter is published.
These staggering figures are at best an underestimate Defining stress
since computer searches rarely go beyond the late
,.

1970s and publications in this field began long before After the completion of my last effort to define stress
this time. Further, the particular search that was used (Levine and Ursin, 1991), I made myself the promise
lists mostly articles and ignores the extensive list of that I would never again engage in what I consider a
futile exercise. One of the more recent definitions was
Tel.: + 1530 752 1887; Fax: + 1530 757 8827; presented by McEwen (2000). "Stress may be defined
E-mail: [email protected] as a real or interpreted threat to the physiological
or psychological integrity of an individual that results The "L" stands for limbic system and is intended
in physiological and/or behavioral responses. In to indicate that the regulation of the hormonal
biomedicine, stress often refers to situations in which cascade caused by exposure to stress involves extra-
adrenal glucocorticoids (GCs) and catecholamines hypothalamic structures. The aim of this chapter is to
are elevated because of an experience." Chrousos and provide a glimpse into the historical events that have
Gold (1992) state "we define stress as state of provided the framework, the insights, and the theories
disharmony, or threatened homeostasis. The adaptive that in many ways still guide our current research.
response can be specific or can be generalized and Insofar as several papers will appear in subsequent
non specific." At the core of these definitions is volumes that deal extensively with many different
the concept of homeostasis. Thus, some disturbance aspects of the HPA axis, I will provide only a very
of homeostasis results in a cascade of physiological simple description of some of the key elements in the
and/or behavioral responses that presumably are neuroendocrine cascade that results in an increased
required to reinstate the ideal homeostatic balance. secretion of adrenocorticotropic hormone (ACTH),
However, these definitions as well as most others and that ultimately results in elevations of the levels
are problematic. As stated by Levine and Ursin of GCs. Some environmental event which involves
(1991) "The major problem with the concept of stress either physical demands or is psychologically
is that we are confronted with a composite, challenging or a combination of both, induces an
multidimensional concept. All existing definitions increase in the release of corticotrophin-releasing
include some components. We can identify three factor (CRF) and arginine vasopressin (AVP) into
main subclasses. These subclasses can be identified the portal circulation. CRF/AVP then activates the
as the input (stress stimuli), the processing systems, corticotrophs in the pituitary to release A C T H into
including the subjective experience of stress and the the general circulation. ACTH acts upon the adrenal
output (stress responses). One basic difficulty is that cortex to induce synthesis and increased secretion of
these subclasses interact. The essential picture we the GCs. Under normal circumstances these elevated
want to convey is one of a complex system with levels of GC activate the GC receptors which serve
feedback and control loops, no less but no more to terminate the release of CRF and ACTH, thus
complicated than any other of the body's self- returning the organism to its basal state.
regulated systems. This system affects many other Traditionally, a discourse on the history of this
biological processes and may function as a common or any other field would trace the evolution of the
alarm and drive system, whenever there is a real or critical components along some time dimension. If I
apparent challenge to the self-regulating systems of were to take this approach the result would simply be
the organism." a compilation of the information contained in many
Steptoe (2000) has suggested that "the effects other sources. Since history does unfold through time
of stress are manifest in four distinct domains; it is difficult to avoid using a temporal framework.
physiology, behavior, subjective experience, and However, I intend to trace this history as it unfolded
cognitive function. The physiological effects of stress in my academic lifetime and how it influenced and
include alterations in neuroendocrine, autonomic shaped the field as we know it today. This will be an
nervous system and immune function." If one were historical perspective, but the perspective will be
to isolate only the physiological effects of stress, the autobiographical.
history of three major areas of investigation would
need to be covered and this would not include
the relationships or lack of relationship among Not so ancient history
these systems. This historical perspective will focus
primarily on the neuroendocrine system and more As was stated earlier I will not attempt to present all
specifically with the hypothalamic-pituitary-adrenal the details of the variety of thought and experimental
(HPA) axis. For this discussion we will use the more evidence that eventually leads us to the 21st century
traditional designation HPA, although more recently views of stress. The earliest references to the concept
we have seen a trend to label the axis as LHPA. of homeostasis come from the Greek philosophers
and physicians, in particular, Hippocrates. This is used the term stress in a biological context. Although
best summarized by Chrousos et al. (1988). What it is a common belief that Selye was responsible for
is important is that the concepts of harmony and introducing the term (Medvei, 1982), Sapolsky (1994)
disharmony (homeostasis?) of man and animals with contends that it was indeed Cannon (1914) who was
both the external and internal environment have responsible. However, Selye was clearly responsible
long been a concern of serious thinkers. The concept for popularizing the concept and bringing it to the
of stress was originally taken from the dynamics of attention of the biomedical community and the
physics to describe the relationship between stress general public.
and strain in an elastic body. "The term stress is The history of science is replete with examples of
applied to the mutual actions which take place serendipity. Sapolsky (1994), in what I consider one
across any section of a body to which a system of of the best written popular books on stress, describes
forces is applied. The term strain is applied to any the origins of Selye's observations as follows: "To be
changes occurring in the dimension or shape of a only a bit facetious, stress physiology exists only
body when forces are applied" (Duncan and Starling, because this man (Selye) was both a very insightful
1959). scientist and somewhat inept at handling rats."
However, our current interest in and views on Originally Selye was attempting to discover the
the physiology and psychology of stress are of more function of some extract of ovarian tissue. However,
recent vintage and can be traced primarily to the "he attempted to inject his rats daily, but apparently
contributions of Walter B. Cannon (1914, 1915, with not a great display of dexterity. Selye would try
1932) and Hans Selye (1950, 1956). The overarching to inject the rats, miss them, drop them, spend half
principles that emerged from the studies by Cannon the morning chasing the rats around the room or visa
and Selye were: (1) there was a physiology that was versa, and so on. At the end of a number of months
specific to stress and (2) that an integral part of this of this, Selye examined the rats and discovered
physiology was related to some function of the something extraordinary: the rats had peptic ulcers,
adrenal. Although both emphasized the role of the greatly enlarged adrenals, and shrunken immune
adrenal, there was a clear distinction between them. tissues. He was delighted; he had discovered the
(1) Cannon focused primarily on the sympathetic effects of the mysterious ovarian extract." However,
nervous system, including the adrenal medulla, following several subsequent presumably control
and the role of the adrenal medullary hormones, experiments the physiological manifestations of
epinephrine also called adrenaline and noradrenaline, these procedures continued to be evident. This led
in the response to emergency situations. Selye, Selye (1936) to postulate that the response to stress
in contrast, emphasized the hormones of the adrenal was nonspecific. Thus, a wide array of stimuli
cortex, primarily the GCs. (2) Canon was describing (stressors) resulted in a similar set or responses and
the responses to an acute threat, whereas Selye was that eventually exposure to stress will result in illness.
concerned with the adaptation of the organism to Selye (1949) defined the General Adaptation
chronic challenges. (3) For Canon, stress was defined Syndrome (GAS) as the "Physiological mechanism
in terms of the stimulus required to elicit these which raises the resistance to damage as such." The
responses. Selye described a triad of responses that GAS consisted of a three-stage reaction to stress, an
he hypothesized constituted stress: hypertrophy of the alarm reaction, a stage of resistance, and a final stage
adrenal, stomach ulceration, and involution of the of exhaustion. It remains one of the more robust
thymus gland. This triad of responses implicated theories in the stress field, although it was in fact
the endocrine, autonomic, and immune systems. incorrect in many of its assumptions. I should state
Stress was defined in terms of the response. Selye in that I come to praise Selye not to bury him. The
fact turned the original physical definition of stress impact of Selye cannot be measured in the specific
on its head. Instead of strain being produced by details of his work and theories. He pioneered and
stress, he did not use the term strain, and assumed launched a field of investigation that has had an
that stress was produced by stimuli he referred to as enormous influence on biology and medicine and is
stressors. There is some controversy over who first still growing at an exponential rate.
 There were a number of developments in the field Although the Selye's definition of stress was to
that followed shortly after Selye's early publications dominate the thinking and direction of stress research
that cast doubt on some of the fundamental aspects for many years, there were other groups of
of Selye's theories and led to a decline in the interest investigators that had a very different perspective.
in GC physiology. One of Selye's claims was that In the late 1940s and early 1950s, one of the bastions
the excess secretion of adrenocortical hormone of biological psychiatry was located at the Michael
would cause arthritis, allergies, and collagen-related Reese Hospital in Chicago. This group had under-
disorders. However, Hench et al. (1949) demon- taken a large study of normal human subjects who
strated that the GCs had profound anti-inflammatory were volunteers in the US Army undergoing airborne
activity and could be used therapeutically to treat training. The definition of stress used in the context
some of these pathologies. One of the coauthors on of this study was "Any stimulus may in principle
this paper was Kendall, who was awarded the Nobel arouse an anxiety response because of the particular
Prize for determining the structure of the steroid meaning of threat it may have acquired for that
hormones. These findings were paradoxical to what particular individual. However, we distinguish a
Selye had proposed. That there is a relationship class of stimuli which are more likely to produce
between stress and illness is now extensively disturbances in most individuals. The term stress
documented, as is the relationship between stress is applied to this class of conditions, thus, we can
and GCs. What is not clear is the relationship conceive of a continuum of stimuli differing in
between the GCs and illness. meaning to the organism and in their anxiety-
The history of science is a history of great ideas producing consequences. At one end are such stimuli
and advances in technologies. The techniques that or cues, often highly symbolic, which have meaning
were available to the stress researcher during the only to a single or limited number of persons and
embryonic phase of the field were at best crude and which to the observer appear as innocuous or trivial.
often laborious. There were no known methods for At the other end are such stimuli, here called stress,
directly measuring the levels of circulating hormones. which by their explicit threat to vital functioning and
The physiology of the stress response was based their intensity are likely to overload the capacity of
initially on changes in weight of the adrenal and most organisms coping mechanisms.
counts made of the circulating lymphocytes and Anxiety has been defined in terms of an affective
eosinophils in blood. The first direct biochemical response; stress is the stimulus condition likely to
measure was the depletion of ascorbic acid in the arouse such responses. Ultimately, we can truly speak
adrenal. It had been observed that, following an of a stress situation only when a given response
injection of ACTH or stress, there was a drop in the occurs, but for schematic purposes as well as
content of adrenal ascorbic acid within the adrenal. consistency with common usage, we may use the
This observation was to be the basis for an ACTH term stress to designate certain kinds of stimulating
bioassay developed by Sayers (1950). There were conditions without regard to response." (Basowitz
many limitations to these indices of adrenocortical et al., 1955). This definition stands in direct contrast
activity. At best they were crude and only by to the one proposed by Selye. In this instance stress is
inference could they be related to the output of the defined almost exclusively in terms of the stimulus
GCs. It was difficult to obtain a time course since only with expectations that these events will evoke some
the measures of eosinophils did not require sacrificing response. For Selye, stress is only stress if the
the animals, and therefore the dynamics of the triumvirate of physiological responses is elicited.
adrenal response were difficult to ascertain. It was not Thus far none of the definitions of stress have
until the 1950s (Silber et al., 1958) that the first direct focused on or even mentioned the brain although
measurement of the adrenal steroids was available. inherent in the psychological approach to stress was
However, despite these limitations, many of the initial the notion that stimuli could be interpreted differen-
observations, hypotheses, and theories have held up tially based on a host of experiential factors, which
remarkably well, which is a testimony to the brilliance implies some process by which the stimuli are
and insightfulness of the founders of this field. evaluated.
The brain: the birth of neuroendocrinology As I discovered years later Geoffrey had little regard
for psychology and/or psychologists. The only useful
In 1948 Geoffrey W. Harris published a paper entitled activity for an experimental psychologist was the
"Neural Control of the Pituitary Gland." This was study of sex behavior, and since I had been the first
followed in 1955 by an expanded monograph with the postdoctoral applicant with behavioral credentials
same title (Harris, 1955). At the time this book was it was obvious that I knew how to examine sex
published, Harris was the Fitzmary Professor of behavior. After several months watching rats with a
Physiology at the Institute of Psychiatry, Maudsley well-worn description of rat sexual behavior written
Hospital, London. He was to become the Professor by Frank Beach, I did learn how. In the end what
of Anatomy at Oxford University until his very began as a nightmare turned out to be a fulfillment
untimely death at the age of 57. I was privileged to of a dream far beyond my expectations and was to
have been a student of Harris from 1960 to 1962 and shape the remainder of my scientific career.
continued my relationship with him until his death. It would be erroneous to imply that neuroendo-
I cannot recall any time that was more exhilarating in crinology was born with the publication of Harris'
the course of my professional career. Every discovery extremely influential paper and monograph. There
was major advance, every important scientist at the were numerous suggestions and hypotheses that
time came through the laboratory, and it was a new postulated a relationship between the brain and the
way to look at the world. Geoffrey Harris was many endocrine system. Harris did not readily embrace the
things to me. He was my hero, my mentor, my friend, concept of neuroendocrinology. For him the brain
and my squash instructor. An excellent description of was an endocrine organ and therefore neuroendo-
him as a scientist and as a man is contained in the crinology was a redundancy. Hippocrates in his
book by Nicholas Wade "The Nobel Duel" (1981). discourse on the glands anticipated this perspective
At the time the "Neural Control" book was many centuries ago when he wrote "The flesh of the
published, I was a young faculty member in a new glands is different from the rest of the body, being
research unit that has just been opened in the spongy and full of veins; they are found in moist parts
psychiatry department at Ohio State University. I of the body where they receive humidity.., and the
had been there only a few years when I encountered brain is a gland as well as the mammae" (Medvei,
the Harris volume. For me this was a revelation, 1982). In 1936 Francis Marshall concluded in
a new approach, whereby there was at last a way to his discussion of periodicity in reproduction that
link behavior with endocrinology. I applied for a "the primary periodicity is a function of the gonad,
postdoctoral position in his laboratory in London, the anterior pituitary, acting as a regulator, and the
was accepted, and packed my wife, three very small internal rhythms adjusted to the environment, by the
children, and one large dog and off we went. We latter acting on the pituitary, partly or entirely,
had numerous adventures along the way, but the through the intermediation of the nervous system"
fateful day arrived in March 1960 when I first (Marshall, 1936). The role of the brain in the
encountered the laboratory. After meandering regulation of reproductive processes was critical in
through the grounds of the Maudsley Hospital I the development of neuroendocrinology. Implicating
finally came upon two rather shabby looking the central nervous system (CNS) with regards to the
temporary structures that was the Laboratory of regulation of the adrenal cortex did not occur until
Neuroendocrinology. I was both surprised and several years later.
depressed. My vision based upon my image of the One of the early models concerning the regulation
greatness of the man in charge led me to expect a of adrenocorticotropin (ACTH) secretion and the
physical plant that would be commensurate with his secretion of GCs from the adrenal proposed that
stature. One could not swing a fat cat or even a ACTH secretion is regulated by the systemic blood
skinny one in the laboratory that was assigned to me. levels of epinephrine. Epinephrine or adrenaline, as
To add further to my depression, Harris wanted me it was then commonly called, was proposed as the
to work on a problem related to sexual differentia- corticotrophin-releasing factor (CRF). The principle
tion, a far cry from my passion for stress and anxiety. proponent of this view was Long (1947, 1952).
In response to stress, the increased secretion of frozen, surgically insulted, subjected to electric shock,
adrenaline by the adrenal medulla acts directly on the injected with toxic agents, irritants, hemorrhaged,
pituitary gland to induce the secretion of ACTH. an and this does not come close to an exhaustive list.
alternative view of the regulation of ACTH was That the peripheral responses to this wide variety of
presented by Sayers (1950). He proposed that ACTH stimuli were similar supported Selye's view of the
secretion is regulated by the blood levels of GCs. nonspecificity of the stress response.
Under conditions of stress the peripheral tissues Studies were beginning to appear that challenged
utilize these hormones more rapidly. The blood the view that all stress was equal, and at the same
content of the GCs falls rapidly as a consequence, time implicated the CNS as critical for the regulation
and this in turn directly stimulates anterior pituitary of the pituitary. Fortier (1951) transplanted pituitary
to secrete increased amounts of ACTH. According tissue to the anterior chamber of eye. This was a
to this view, the anterior pituitary and the adrenal favorite transplantation site for the obvious reason
cortex form a self-regulating system, the balance of that this area is heavily endowed with a rich blood
which is broken mainly by variations in the activity supply, though I have commented that the real
of the peripheral tissue. purpose was to better visualize the pituitary. Fortier
The position held by Long and coworkers would exposed the animal with the transplanted pituitary
not withstand the scrutiny of subsequent experi- to several stress-inducing stimuli. He divided them
mental examination. There was no question that into two groups: (a) systemic stress which included
injections of adrenaline could stimulate ACTH injection of adrenaline or histamine, exposure to
secretion. It did not appear, however, that it was cold and (b) neurotropic stress, which included
absolutely essential. Amongst the experiments that exposure to loud sounds and immobilization.
challenged the adrenaline hypothesis, perhaps the Fortier reported that systemic stress was able to
most damaging was an experiment conducted by elicit an ACTH response in animals bearing a
Marthe Vogt (1952), who also stands as one of my transplanted pituitary, but that in the case of
heroes. She determined that enucleating the adrenal neurotropic stress there was no indication of ACTH
medulla reduced circulating levels of adrenaline to release. Fortier argued that the so-called neurotropic
close to zero. However, in response to emotional stress required the mediation of the CNS in order
stress there was a fall in adrenal ascorbic acid in the to release ACTH, whereas the response to systemic
adrenal demedullated rat that followed an identical stress may be mediated by other blood-borne factors.
time course to those of intact animals. Similar results There were other studies that suggested that stress-
were reported by Hodges (1953), effectively dismiss- inducing stimuli could be differentiated. Dallman
ing the hypothesis that adrenaline was the CRF. (1979) summarized a number of experiments and
Regulation of ACTH secretion based upon the classified the different stimuli into those in which the
level of circulating adrenal hormones was to suffer a adrenal response was blocked by the pretreatment
similar fate. Although the evidence that supported with a single dose of GCs (GC sensitive) and those
Sayers indicated that blood levels of the adrenal that still elicited a response after pretreatment
hormones do in part regulate the output of ACTH, with large doses of GCs (GC insensitive). Feldman
there were many facts that could not be explained (Feldman et al., 1970; Feldman, 1985) reported that
by this theory. One example is that this theory could in rats with hypothalamic islands, the GC response
not explain why adrenal atrophy occurs when the to peripheral neural stimulation was inhibited. The
pituitary is transplanted to a site remote from the responses to systemic stress remained intact. That
sella turcica. As long as the pituitary was properly there are differences in the types of stress has been
vascularized it should maintain a normal functional demonstrated by at least three distinctly different
adrenal cortex. procedures, transplants, GC inhibition, and hypo-
The history of stress research in some ways reads thalamic deafferentation. Recent methodological
like a chamber of horrors. Animals were subjected to advances have made it possible to examine the neural
a wide variety of stress inducing stimuli that were to pathways in the CNS in response to different stimuli
say the least massively invasive. They were boiled, that induce increased secretion of corticosterone and
ACTH. Sawchenko (1991) has described at least five it remained viable though largely nonfunctional. The
different pathways that converge on the PVN and experiment by Fortier (1951) described previously is
stimulate the release of CRF. Herman and Cullinan but one example of the importance of the transplant
(1997) have presented the most recent version of experiments in proving the neuroendocrine hypothe-
the stress dichotomy. They state "Stressors involving sis. A more direct approach intended to show the
an immediate physiologic threat ('systemic stressors') importance of the portal system was that of
are relayed directly to the PVN, probably via sectioning the portal vessels. Under these conditions
brainstem catcholaminergic projections. By contrast, the pituitary remained in situ, but was deprived of the
stressors requiring interpretation by higher brain blood flow from the hypothalamus. One of the goals
structures ('processive stressors') appear to be I had set for myself when I went to the Harris
channeled through limbic forebrain structures." laboratory was to learn the technique of sectioning
At the core of Harris' theory was the hypothesis the portal vessels. It did not take long to realize that
that the pituitary gland was regulated by blood-borne the surgical skills involved were far beyond my
chemical substances that were transported via the abilities. Harris' surgical skills were legendary. In the
portal vessels from the hypothalamus to the pituitary. early stalk-section experiments although there was
The growth of neuroendocrinology was slowed down unambiguous evidence that the ACTH secretion was
initially by the description, by Popa and Fielding seriously impaired, after a relatively short period of
(1930), that the blood flowed from the pituitary to the time the pituitary once again became functional. The
hypothalamus. If the blood flow was from south to reasons for this appeared to be the capacity for the
north, then the question of how the hypothalamic portal vessels to show remarkable regeneration. If
hormones could be transported to the pituitary gland regeneration was prevented by placing a wax paper
was an enigma. Subsequently, it was demonstrated barrier between the cut ends of the stalk (Harris,
(Wisloski, 1937; Harris, 1947) that the blood flow 1950), then the release of ACTH was continually
through the portal vessels could indeed flow from impaired. I continue, even though many years have
the hypothalamus to the pituitary, thus making it elapsed, to be impressed by the simplicity and
possible for the brain hormones to directly commu- elegance of these studies. By using basic physiological
nicate with the pituitary. logic and with some surgical magic, the major tenants
Harris postulated a specific releasing factor for of neuroendocrinology were established.
each of the pituitary hormones. The term "releasing In addition to the experiments which disrupted
factor," to describe the substances in the hypothala- the blood-borne communication between the hypo-
mus that could induce secretion of the pituitary thalamus and the pituitary, there were other lines
hormones, had been already proposed by Schally. of investigation that presented convincing evidence
Harris used two different approaches to prove that that the brain was directly involved in regulating
the regulation of the pituitary was a consequence of ACTH. (1) Hypothalamic lesions." Numerous experi-
hormones being transported via the portal circula- ments (Porter, 1953; McCann, 1953) were reported
tion. These were (1) pituitary transplants and using animals bearing lesions in the hypothalamus.
(2) pituitary stalk sections. That endocrine organs These studies indicated that hypothalamic lesions
could be removed from their original anatomical prevented the ACTH response to most stressors.
location and remain viable had history in experi- Many of these lesion studies failed to support the
mental endocrinology, dating back to the work of conclusions of Fortier that the response to systemic
John Hunter (1728-1793). Harris utilized these stress did not require CNS involvement. Lesions
techniques to demonstrate that in order for the which obliterated the hypothalamus prevented the
pituitary to function normally the communication release of ACTH to all stimuli. I use the term
between the hypothalamus and the pituitary via obliterate to indicate the state of the art for making
the portal vessels had to be intact. When the pituitary lesions. Most of the early lesions studies usually
was transplanted to a site remote from the produced large, massive lesions making it difficult
hypothalamus (Harris and Jacobsohn, 1952), as to specify which if any of the specific nuclei in the
long as it was adequately supplied with blood, hypothalamus was responsible for the secretion
10

of the putative CRF. (2) Electrical stimulation of the responsible for activating ACTH focused on the
hypothalamus: On my first tour of the laboratory in hypothalamus. During the early 1950s several
London I was given the "grand" tour. I was ushered investigators independently reported that the extracts
into a large room which contained a large circular of hypothalamic tissue could stimulate the release
arena. Seated in this arena was a rabbit with of ACTH from anterior pituitary cell in vitro.
something implanted in its skull. The outer part of Ironically, although the initial attempts to isolate a
this contraption appeared to be something resem- releasing factor centered on CRF, it proved to be one
bling an electrical coil. I was informed that this of the most difficult and elusive of all of the major
apparatus (I use this term kindly) was presenting hypophysiotropic hormones in the CNS. The pitfalls
electrical stimulation directly to the hypothalamus on on the way to the CRF were many. There were
the assumption that the electrical pulses would elicit a problems with obtaining sufficient hypothalamic
response from the hypothalamus that would result in tissue needed to extract and analyze adequate
the release of the tropic hormones for the pituitary. quantities of material. My introduction to
Despite its Rube Goldberg appearance this procedure Guillemin was in 1961 during my first visit to Paris.
produced some of the most convincing data that the I traveled to Paris with a fellow postdoc from
hypothalamus was intimately involved in the regula- London, who had been an associate of Guillemin
tion of pituitary hormones in general and ACTH at Baylor. Guillemin had recently arrived in Paris
specifically (deGroot and Harris, 1950). and had established his laboratory at the very
prestigious College de France. At first glance he
had achieved the prominence and all that went
The CRF quest with it that a young scientist could ever hope for.
He lived in part of a lovely chateau with beautiful
Given this background and the growing acceptance grounds on the outskirts of Paris. Unlike the
of the role of the brain in regulating ACTH, it is laboratory in London, this lab was sparkling and
not surprising that during the period of time when replete with all the latest technology, but what was
neuroendocrinology was blossoming there should most impressive was the very large freezer which
also be a growing interest in attempting to find the contained thousands and thousands of sheep
chemical substance in the hypothalamus that was hypothalami that Guillemin had obtained from the
responsible for activating ACTH. The names most slaughter houses of France.
associated with the first attempts to describe CRF There were numerous problems that were encoun-
were Roger Guillemin and Andrew Schally, who tered in attempting to isolate and characterize CRF.
were awarded the Noble Prize in Medicine in 1977 Hypothalamic extracts often contained other, weaker
for their identification of TRH and LH-RH. The secretagogues of ACTH such as vasopressin, cate-
relationship between these two men on the way to cholamines, etc. Another major obstacle was the
Stockholm is legendary and well documented in claim (McCann and Brobeck, 1954) that in fact the
Nicholas Wade's book "The Nobel Duel." In CRF was in reality vasopressin and there was little
addition to describing much of the persona and need to try to identify a novel substance. The
background of Guillemin and Schally and the similarities in the size of ACTH (39 amino acids) and
intensity of the animus between them, it is perhaps what ultimately turned out to be the size of CRF (41
the best written and most entertaining history of amino acids) was not conducive to easy separation of
neuroendocrinology. the peptides by the existing methods. It also turned
Since most of the evidence indicated that the out to be the case that the structure of CRF was
communication between the hypothalamus and much more complex than other hypophysiotropic
pituitary was by some blood-borne factor, it should hormones. Thyrotrophic-releasing hormone (TRH),
be possible to find the compound and characterize for example, contains only three amino acids.
its structure. Previously it was mentioned that the Concentrating on the identification of CRF proved
first proposed CRF was adrenaline secreted by the to be a quagmire in the hormone-releasing enterprise.
adrenal medulla. The search for the new secretagogue In his conclusions to the chapter describing the quest
for CRF, Wade wrote "To this day, CRF has not a specific releasing factor for each of the pituitary
been found, and may not even exist as such." hormones. We now know that there are hypo-
However, at almost the identical time this thalamic inhibiting as well as releasing hormones.
statement was uttered, Vale et al. (1981) at the Salk Vasopressin may not have been the CRF but it is an
Institute reported the isolation, characteristics, active cosecretagogue.
synthesis, and in vitro and in vivo biological activity Once it became doctrine that the regulation of the
of a 41-amino acid ovine hypothalamic CRF. This pituitary tropic hormones was via some blood-borne
was a testimony once again to perseverance, but also substance synthesized in the hypothalamus and
to the major advances in the available technology, released into the portal circulation, there were
amongst them being the development of the radio- other investigators who attempted to characterize
immunoassay (RIA) for peptide hormones, advances the structure of these hormones. However, only
in molecular biology, ion exchange, and liquid Guillemin and Schally were willing to take the big
chromatographic techniques. In one way the quest gamble and devote all of their time and resources that
for CRF was finally over and yet in another way it resulted in the identification of the first releasing
has just begun. Several years after presenting the factors and ultimately to the discovery of CRF and
structure of CRF, Vale reported the cloning of the the CRF-like peptides.
CRF1 receptor and further the identification of
additional CRF2 receptors which has resulted in the
discovery of at least three new and distinct CRF-like GCs
p e p t i d e s - Urocortin 1, 2, or stress copin-related
peptide and Urocortin 3 also known as stresscopin We have thus far discussed some of the milestones
(Hsu and Hsueh, 2001). The functional significance that were crucial in the establishment of neuroendo-
of these peptides is only beginning to be described crinology as a discipline. However, when we trace the
(Dautzenberg and Hauger, 2002). history of stress research it began with the adrenal
CRF, however, has proven to be a remarkable cortex, and although the peptides in the brain appear
molecule. Not only is it found in abundance in the to have multiple functions, at least one of the major
paraventricular nuclei (PVN) of the hypothalamus, functions of CRF is to regulate the secretion of
but it is widely distributed throughout the brain and ACTH and GCs. Conversely, the adrenal hormones
the periphery. CRF is also involved in the regulation in turn regulate the synthesis of CRF by the way of a
of a broad range of physiological and psychological negative-feedback mechanism. Any basic textbook of
processes. Amongst these is the modulation of the endocrinology presents a detailed description of
autonomic system, gastrointestinal activity, behavior, most, if not all, of the known physiological actions
and immune function. CRF has also been implicated of the GCs and the dire consequences of either under
in a variety of psychiatric and other neurological or overproduction of these hormones. Previously we
disorders. Thus, what began as the search for a discussed the developments that focused on the
hypothalamic hypophysiotropic hormone may even- response of the adrenal as a central component of the
tually extend into many areas of pathophysiology stress response. However, Sapolsky et al. (2000) state
that are not immediately associated with the that "Few contemporary endocrinologists view the
regulation of the pituitary-adrenal axis. GC actions as part of a coherent physiological
I stand in awe of many of the intellectual giants picture, or see the need to. Today the focus is on the
that were involved in the ontogeny of neuroendo- molecular and cell biology of GC action, e.g., GC
crinology. Although the specifics of the hypotheses receptors as ligand-activated transcription factors or
and theories may not have been entirely correct, they GC-induced apoptosis in lymphocytes."
each in some way contained elements that have What has been, and still is to some extent, one
proven to be prophetic. Peripheral adrenaline was not of the important questions that plague the stress
the CRF, but the catecholamines are clearly part of researcher is what the adaptive significance of
the neuroendocrine cascade that activates the release increased GC secretion is? It is not difficult to
of the peripheral stress hormones. Harris postulated understand the importance of GC when the organism
12

is confronted with acute life-threatening and physi- actions did not receive much attention due to the fact
cally invasive events. Under these circumstances the that it was originally published in the house organ of
HPA axis is an exquisite adaptive mechanism. Organon Pharmaceuticals. In a now well-quoted
However, in our contemporary view of stress there metaphor he viewed stress as a fire and that the
is as much, if not more focus, on psychological and function of the GCs was to limit the water damage
social stress as on the physical. created by the fire fighters. This view of the role of
The question of how GCs influence the stress GCs in the stress response remained obscure until
response continues to be an issue that has still not many years later when Alan Munck wrote a classic
been completely resolved. Historically there have paper that independently proposed that GCs role in
been several critical hypotheses that have guided the the stress response was to exert a suppressive action.
way we view this problem. Originally Selye specu- Munck et al. (1984) wrote "We propose that: (a) the
lated that GCs facilitate or mediate the ongoing stress physiological function of stress induced increases in
response. One of the pioneers in GC physiology was GC levels is to protect not against the source of stress
Dwight Ingle. Ingle was an important member of itself, but against the normal defense reactions that
the group at the Mayo clinic and contributed the are activated by stress; and (b) the GCs accomplish
bioassay that was used to test the purified fractions of this function by turning off those defense reactions,
the adrenal cortical hormones that were eventually thus preventing them from overshooting and
characterized by this group. He also was amongst themselves threatening homeostasis." Thus we begin
the first to demonstrate negative feedback when he to see an integrated set of functions that are all
observed that administration of adrenal cortical part of the complex actions of the GCs in the stress
extracts or purified GCs caused atrophy of the response. Recently, Sapolsky et al. (2000) have
adrenal gland that could be reversed by simultaneous attempted once again to answer the question "How
administration of pituitary extracts. One of his major do glucocorticoids influence the stress response." In
contributions was to propose a new and unique this chapter the previously proposed actions of the
function for the GCs. The assumption that prevailed GCs, stimulatory, permissive, and suppressive, are
in the stress literature was that the damaging effects integrated along with another newly proposed
of stress were due to hypersecretion of the adrenal function of the GCs, "preparative."
cortex. Ingle (1952) showed that the characteristic It has been over 30 years since McEwen et al.
damaging effects of stress persisted when the GCs (1968) injected adrenalectomized rats with radio-
were supplied to the adrenalectomized animals at a active GCs and observed that the GC was retained
constant, but not excessive rate of administration. in high levels by the hippocampus as well as other
From these observations he deduced that the role of regions of the limbic forebrain. Although it is beyond
the GCs in stress appears to be due to a subtle the scope of this chapter to cover the molecular
"permissive" or supporting role rather than as the biology of the GCs, one of the most influential
primary mediator of the stress reaction. The most developments in our attempts to understand the
recent definition of the permissive action is "permis- physiology of the GCs was the discovery of the GC
sive actions are exerted by GCs present before the receptors, their anatomical distributions, structure,
stressor and prime the defense mechanisms by which and functions. Steroid hormones are a privileged
an organism responds to stress. Their consequences class of molecules that have direct access to the brain
are first manifested during the initial stress response and the brain is a target organ for these hormones.
and occur whether or not there is a stress-induced One of the surprises occasioned by the McEwen
increase in GC concentrations" (Sapolsky et al., et al.'s results was the hippocampal localization of
2000). Thus the GCs were now relegated to an the GC. There was little evidence at the time that the
essential, but a more supportive role. hippocampus was associated with neuroendocrine
Around the same time a Dutch physiologist/ function. The presence of GC receptors in areas of the
pharmacologist, Marius Tausk, proposed another CNS other than the hypothalamic and preoptic areas,
role for the GCs. He suggested that GCs exerted a which were known to have direct neuroendocrine
suppressive action. However, Tausk's view of GC functions, indicated that the effects of the GC on
 13

the CNS may extend beyond its presumed role in and facilitate the return to basal levels. Well before
the regulation of the stress response and that GC the discovery of the GC receptors there was
may influence those functions, spatial learning and considerable work that described the different aspects
memory, that have been ascribed to the hippocam- of GC negative feedback (Jones et al., 1972; Dallman
pus. Since the original observation there has been and Jones, 1973; Dallman, 1979) and postulated that
considerable progress in GC receptor research. A reactive negative feedback occurred in three different
further significant development was the findings of modes, fast, intermediate, and slow. According to
Reul and deKloet (1985) that there were two distinct Dallman (2000) "fast effects occurs in milliseconds
types of GC receptors. Based primarily on studies and must be exerted at the cell membrane,
which examined the cytosol-binding properties of 'intermediate feedback has its onset at about 30min
these receptors, there appeared a high-affinity receptor after a pulse or continuous exposure to steroid and
which was occupied by low levels of GCs and a low- last about for a period of hours', slow feedback is
affinity receptor which required levels of GCs that are found in conditions in which supraphysiological
present only at the peak of the circadian rhythm or levels of exogenous GC have been provided for days
when elevated due to stress. Originally these two or weeks."
receptors were designated as type 1 and type 2, but The unique anatomical distribution of the MRs
in recent years type 1 is referred to more frequently has caused the field to examine a much broader range
as mineralo-corticoids (MR) and type 2 as gluco- of possible effects of GCs on brain function including
corticoids (GR). Since McEwen used tracer amounts cognition. One example is the studies that suggest
of radiolabeled GC, the receptors that were found in that the ratio of M R / G R appear to be involved in
the hippocampus were most likely the high affinity depression (Young et al., 2003). As we begin to
MRs and not GR. Although both types of receptors determine the many ways that the GCs influence the
can be found in the hippocampus, the MR is more brain, these hormones have and will continue to
localized anatomically whereas the GR is more widely move beyond their simple designation as stress
distributed throughout the brain. The development of hormones. The history of the stress and the HPA
specific steroid agonists and antagonists firmly establi- system is, when thought of in real time, relatively
shed that the receptors located in the hippocampus recent. It should not come as surprise that many of
were indeed MR. The cloning of these receptors the individuals that have been mentioned as historical
demonstrated that each form was the product of a figures are now the leaders in the field. Notably
distinct gene. de Kloet et al. (1998) present a table amongst these are Mary Dallman, Bruce McEwen,
indicating the "milestones" in GC receptor research. E. Ron de Kloet, and Wylie Vale.
Although their last entry is 1996, I doubt that we
have seen the end of new contributions to this field.
What makes the discovery of two distinct GC Psychoneuroendocrinology
receptors in the brain important is that it created a
different approach to our view of the actions of GCs. In 1970 I attended the inaugural meeting in New
de Kloet et al.'s (1998) hypothesis is that the "tonic York City of a newly formed society, which had been
influences of corticosterone are exerted via hippo- named the International Society of Psychoneuro-
campal MRs, while the additional occupancy of GRs endocrinology. The name was indeed daunting, but
with higher levels of corticosterone mediate feedback there was a group of people who believed that the
actions aimed at restoring disturbances in homeo- relationship between psychology, psychiatry, and
stasis" (de Kloet and Reul, 1987). de Kloet et al. endocrinology had advanced to the point where a
(1998) further posited two modes of negative feed- new forum for the dissemination of information
back which are implied in his hypothesis. (1) regarding these relationships was necessary.
"proactive" negative feedback mediated via the Psychoneuroendocrinology is a broad-based disci-
MR maintains normal variations due to circadian pline that examines the relationship between brain,
rhythms and (2) "reactive" feedback operating via behavior, and numerous endocrine and immune
the GR serves to inhibit further secretion of ACTH systems. The psychobiology of the HPA axis is
14

an integral part of psychoneuroendocrinology. Once Early experiences

again it is almost impossible to determine any event
or group of studies that could be considered the That the psychological factors were important in the
catalyst for including psychological factors within the expression of the HPA response to stress long
rubric of HPA physiology. predated the views expressed by Mason. In 1952 I
John Mason (1968, 1975) pointed out that the went as a postdoctoral fellow to the Institute of
most potent stimuli for activating the pituitary- Psychiatry and Psychosomatic Research at the
adrenocortical system were psychological. Mason's Michael Reese Hospital in Chicago. Although my
position was a direct attack on doctrine presented espoused purpose was to be trained as a clinical
by Selye. Mason emphasized the crucial role for psychologist, the fellowship turned out to be very
what he called "the psychological approaches different than I had bargained for. For the first time
involved in the emotional or arousal reactions to I was exposed to the area of stress and also to the
threatening or unpleasant factors in the life situation endocrinology of the HPA axis. It was during that
as a whole." He argued that the so-called non- period we conducted the initial experiment (Levine
specificity of the endocrine responses to stress occurs et al., 1956) that demonstrated long-term behavioral
because of the emotional component surrounding consequences as a result of early postnatal manipula-
the experience associated with exposure to stress- tions. This first experiment examined the effects of
inducing stimuli. Thus, the nonspecific responses postnatal exposure to electric shock as a model for
described by Selye are primarily behavioral or early exposure to trauma on a behavior presumed to
psychological in nature and "the interpretive be a measure of anxiety, the conditioned avoidance
processes underlying the nonspecific bodily response. In addition to pups that were exposed to a
responses probably involves a higher level of CNS brief electric shock (3 min daily starting on day 1 of
function than was previously realized." For Mason life) we included two control groups. One group was
there was only one type of stress, that involving removed from the dam placed in the shock apparatus
some emotional component. This doctrine has for the identical period of time (3min), but not
become known as the "Mason Principle." shocked. The second control group remained in
Hennessy and Levine (1979) hypothesized that the nest totally undisturbed until weaning. The results
the HPA axis was a sensitive indicator of emotional were completely paradoxical to what we had
arousal and therefore its response was a reflection of predicted. The group that was most emotionally
heightened emotional arousal. These views certainly disturbed was the totally undisturbed (nonhandled)
reflect a parochial approach to the psychobiology pups. Thus, the postnatal experience of being
of stress. We now know there are many different removed and separated briefly from the dam, with
pathways that can activate the CRF neuron. or without shock, appeared to permanently modify
However, the hypotheses presented by Mason and the behavioral responses to subsequent traumatic
others were very influential in the growth of events well into adulthood. The first indication that
HPA psychoneuroendocrinology. Once it was brief separations from the dam which became known
accepted that the psychological factors play an as early handling also influenced the HPA system was
important role in the activation of the HPA axis, a study (Levine, 1957) that exposed early handled
it became theoretically possible that the psycho- and nonhandled adults to an injection of glucose
logical processes can also modulate the HPA and examined adrenal weight 24 h after the injection.
response. The psychobiology of stress has many Although basal adrenal weights did not differentiate
faces and one cannot presume to cover all of the between the two early experience groups, adrenal
clinical and experimental data that are germane to weight was significantly increased only in the non-
this topic. The focus in the discussion will handled animals that had received the 20% glucose
emphasize: (1) some of the psychological factors injection. These results were surprising since adrenal
that modulate the HPA response, and (2) the effects hypertrophy following stress usually takes consider-
of some of the hormones that comprise the HPA ably more time to develop than the 24 h that elapsed
axis on behavior. between the injection and removal of the adrenal.
 15

Between 1957 and 1960 we conducted a series of It has always been assumed that the effects of early
experiments that indicated these early experiences handling were to modify those aspects of the CNS
also altered the developmental trajectory of the HPA that regulated the response of the HPA axis. There
axis. These data will be discussed in the chapter were numerous reasons for this assumption. The
(Vazquez and Levine, this volume) on the develop- evidence indicated that there were no differences
ment of the HPA axis. between handled and nonhandled animals in basal
These initial studies did strongly suggest that early levels of corticosterone and ACTH. No differences
experiences have a long-term influence on the activity were observed between the different early experience
of the adrenal and the mechanisms that regulate this groups on adrenal sensitivity to ACTH, pituitary
organ system. Research in this area has continued response to exogenous CRF, or clearance of
for four decades and although many other biological corticosterone and ACTH. Adult early handled and
processes have been investigated, the original findings nonhandled rats have similar levels of corticosterone-
have held up remarkably well. It was not until binding globulin. Insofar as none of the indices of the
almost ten years had passed that the effects of early peripheral aspects of the HPA axis differ as a
experience the HPA axis were revisited. The impetus consequence of early handling, the origins of the
was the development of a reliable biochemical assay differences on the response to stress must be
for examining the levels of circulating corticosterone. a function of some change in programming of the
This fluoremetric assay made it possible to examine central regulatory mechanisms. At least two compo-
the dynamics of the release of corticosterone and to nents of the central regulatory mechanisms have been
obtain repeated measures on the same animal. In the reported to differ between the early experience
years following the introduction of the fluoremetric groups. Plotsky and Meaney (1993) reported that
assay, which was modified to assay corticosterone the resting levels of CRF mRNA in the PVN were
in small quantities of plasma (Glick et al., 1964), significantly higher in nonhandled compared to
numerous studies emanating from many laboratories handled adult animals. Median eminence levels of
studied adrenocortical activity in animals subjected CRF and AVP are also higher in nonhandled rats.
to different early experiences using a multitude of These differences in CRF gene expression and protein
different paradigms. In our laboratory we published levels are apparent under resting conditions, although
numerous studies on the effects of early handling in there are no differences in circulating corticosterone
rats and mice. The effects of early handling on the levels. More recently we have shown that increased
dynamics of the adrenal response to stress have CRF gene expression following restraint is much
proved to be an extremely robust phenomenon. The more rapid in nonhandled rats (Gordon and Levine
initial experiments (Levine et al., 1967) demonstrated 1999). Early handling also markedly changes the GR
that the corticosterone response following exposure receptor density in the hippocampus of adult rats. In
to an open field was significantly reduced in general, early handled animals have increased
early handled animals. This study was conducted in hippocampal GR sites and also show an increased
collaboration with Victor Denenberg whose con- gene expression for the GR receptor. The MR
tributions were vital to the growth of developmental receptors do not appear to change with early
psychobiology. These findings have been robust and handling. Bhatnagar et al. (1996) suggest that "it
reproduced under a variety of different conditions seems that the increase in GR sites is a critical
(Meaney et al., 1993). The adrenocortical responses feature of neonatal handling on HPA function. This
to novelty, restraint, shock, conditioned taste increased receptor density appears to increase the
aversion, etc. all have been shown to be significantly sensitivity of the hippocampus to circulating GCs,
reduced in early handled animals. Further, early enhancing the efficacy of negative feedback inhibition
handled animals appear to have a more efficient on HPA activity, and serving to reduce post-stress
negative feedback regulation. Early handling also secretion of ACTH and GC in handled animals."
modifies the response to neonatal malnutrition Although there have been several hypotheses
(Wiener and Levine, 1978) and fetal alcohol proposed to account for the effectiveness of early
syndrome (Weinberg et al., 1995). handling, one hypothesis that seems to have received
16

the most attention and support from the existing data endocrine responses to stress in the offspring. In
is the "maternal mediation" hypothesis (Smotherman particular, increased licking/grooming and arched
and Bell, 1980). Intuitively, it was difficult to back nursing are correlated with a reduction in HPA
understand why the seemingly innocuous manipula- activity and less-fearful behavior in the offspring. They
tion of very brief bouts of maternal separation could further demonstrated that variations in maternal care
have such permanent and pervasive influence on serve as the basis for nongenomic behavioral trans-
behavior and the HPA axis. The first suggestion that mission of individual differences in stress reactivity.
the effects of early handling could be maternally In recent years new paradigms have been
mediated was an experiment by Denenberg and introduced in an attempt to investigate the effects
Whimbey (1963). These investigators reared pups of adverse early experiences on the neurobiology of
with mothers who had no prior early interventions stress. Several laboratories have begun to explore the
and compared them to offspring of mothers who had consequences of more prolonged periods of maternal
been handled as infants. Elaborate cross-fostering separation (Plotsky and Meaney 1993; Patchev et al.,
procedures were included in an attempt to tease out 1997). Although there are only a limited number of
postnatal from prenatal effects. The results indicated published papers using these paradigms, it does
that, on some measures of emotionality, the early appear as though these longer periods of separation
experience of the mother significantly altered the can reverse the effects of brief separations (early
behavioral outcome measure. On other indices handling). In some instances these animals as adults
of emotionality the effects were a result of the exhibit hyperreactive HPA activity in contrast to the
interaction between pre- and postnatal influences. well-established hyporeactivity that results from early
Levine (1967) demonstrated that the maternal handling. Although the ultimate outcome of these
early experience could influence the adrenocortical postnatal manipulations depends upon a number
response of the pups. The corticosterone response to of different variables, there is little question that
novelty of pups reared by handled dams was reduced one major source of individual differences in the
compared to pups reared by nonhandled dams. neuroendocrine regulation of the HPA axis is based
Handling the pups resulted in a reduction of the on the environment during development and that
response when reared by a nonhandled dam. In these effects are pervasive and difficult to reverse.
contrast, handled pups from handled dams did not
differ from their nonhandled counterparts if the
dam had been handled as a pup. There is a direct Stress and coping
evidence that handling altered maternal behavior
(Smotherman et al., 1977). They observed maternal One issue that was confronted early in this chapter
behavior in dams when reunited with pups that was the definition of stress. There was no attempt to
were handled or shocked. Several aspects of maternal arrive at a consensus definition. Also discussed was
behavior were intensified when the treated pups were the pervasive issue that all stress-inducing events do
returned to the dams. Clearly, manipulation of the not fall into simple distinct categories and that there
pup altered and increased dam-pup interactions. are different neural pathways that are activated in
For those of us who have had the opportunity to response to different types of stress-inducing events.
observe the field over an extended period of time, What is now abundantly clear is that events that can
the cyclic quality of science is apparent. Questions be viewed as purely psychological, and do not involve
that were posed decades ago are revisited often any immediate threat to homeostasis, are potent
with new approaches, new techniques, and insights. activators of the HPA axis. With the advent of a
Recently, Meaney and coworkers (Liu et al., 1997; simple noninvasive procedure for measuring cortisol
Francis et al., 1999) have used a naturalistic in saliva, the literature demonstrating that the
approach to the question of maternal mediation. activation of the HPA axis in response to psycho-
They observed maternal behavior in undisturbed logical stimuli has been extensive (Kirschbaum and
females. They reported that variations in maternal Hellhammer, 1994). Further, there is evidence that in
behavior influence the development of behavioral and animals and man the anticipation of an event is as
 17

potent an activator of the HPA axis as the event studies (Weinberg and Levine 1977) reported similar
itself. Phobic patients show the highest elevation of findings. Davis et al. (1977) found declines in
cortisol on the day prior to being exposed to the adrenocortical activity using a lever-press escape
phobic stimulus (Wiedenfeld et al., 1990). What has paradigm that permitted escape but not avoidance of
also emerged from studies in this area is that there are the aversive stimulus. The avoidance component of
large individual differences in response to these the shuttle box task appears to be less important
stimuli. Although some of these individual differences than the ability to make an active response (control)
may be attributable to early experiences, there are that terminates the noxious event. Dess et al. (1983)
other behavioral processes that modulate the examined the issues of control and predictability
responses to psychological stimuli. in dogs. The results revealed that control reduced the
There is abundant evidence that unambiguously cortisol response to shock, whereas predictability in
supports the hypothesis that psychological factors the absence of control has no discernable immediate
are important in determining the endocrine responses effect. Increased circulating levels of cortisol induced
to stress. The field is indebted to Weiss (1972) for his by shock occurred whether or not the shock was
innovative research on stress and coping. What was predictable. Hanson et al. (1976) presented a clear
demonstrated in these studies was that a physio- demonstration that monkeys who could control the
logical response (stomach ulceration), in response duration of a noxious sound reduce the cortisol
to a well-defined stimulus (electric shock), can be response to these loud aversive noise levels. These are
modified: if the animal is permitted to exert control but a few of the many examples of importance of
which regulates in some manner the duration and/or control in modulating the GC and presumably the
intensity of the shock, and/or is presented with neural components of the HPA axis.
information concerning the onset or offset of the The influence of predictability on HPA activity is
shock, predictability, or is given information con- more problematic. Davis and Levine (1982) and Dess
cerning the efficacy of the response, feedback. Weiss et al. (1983) failed to show that predictability in
further postulated that the amount of stress an the absence of control exerted any effect on the
animal actually experiences when exposed to noxious HPA axis. However, these investigators pointed out
stimuli depends on two variables: the number of the interaction between control and predictability.
coping attempts (responses) and the amount of Whereas prediction may occur with or without
relevant feedback these responses produce. control, control in the absence of predictability
Some of these psychological principles are directly is not necessarily true. The very act of making a
applicable to the regulation of the HPA axis. stimulus (or its offset) response contingent dictates
Evidence that control is a potent modulator of that the stimulus will also be predictable.
HPA activity is found in studies using a variety of As we have documented the absence of control
species. Coover et al. (1973) examined corticosterone results in an exacerbated GC response. There is
levels during active avoidance in rats. Plasma samples further evidence that the loss of control can induce
were obtained following the first training session increased HPA activity. In the study by Coover et al.
during which time the rats received shock on the (1973), a procedure was introduced that prevented
majority of the trials, after the seventh training the animal from making the now well-learned
session when the animals have achieved asymptotic avoidance response. During this "forced extinction"
performance, and ten days later. There was a decline period a locked door was placed between the
in plasma corticosterone levels from the first to the compartments. Although the conditioned stimulus
seventh training session, which was attributed to the was presented and shock was omitted, corticosterone
absence of shock. However, as the training continued levels were again elevated compared to the plasma
there was a further decline in corticosterone levels, levels of corticosterone during avoidance condition-
although performance of the avoidance task did not ing. These data were seen to indicate that preventing
differ from the early training. This decline was the rat from making its response-contingent avoid-
interpreted as evidence for the effects of control and ance response represented a loss of control. Another
predictability on the response of the HPA axis. Other example of the effects of loss of control is the rise in
18

corticosterone following extinction of an appetitive axis (Hennessy and Levine, 1979; Levine and Ursin,
response. Rats trained to press a lever for water or 1991). The underlying principle that pervades most
food on a continuous reinforcement schedule show an psychobiological approaches to stress invokes cogni-
elevation of corticosterone levels as a consequence of tive processes. The primary cognitive operation is one
reinforcement being withdrawn during extinction of the comparison between the immediate external
(Coover et al., 1971). These data were interpreted as event and some cognitive representation based on
suggesting that "frustration," defined as the absence prior experiences. When discrepancies occur between
of reinforcement occurring in a context where the event and the cognitive representation, arousal is
reinforcement is expected, does result in activation increased. The neurophysiological basis for this
of the HPA axis. Frustration, however, can also be concept is derived from Sokolov's (1963) theory of
viewed as loss of control. This notion is supported by the orienting response. Insofar as stress and arousal
a study by Davis et al. (1976). Extinction of an appear to be analogous concepts (Hennessey and
instrumental response can be achieved in several Levine, 1979), those events that serve to increase
ways. The traditional procedure is to permit the arousal should activate the HPA axis and those, which
animal to respond and omit the reward. Another would reduce arousal, should result in inhibition.
extinction paradigm is to permit the subject to Thus, such notions as uncertainty, expectancies,
continue to respond and receive reward, but to response outcomes, etc. have all been invoked to
make obtaining the reinforcement no longer response deal with the manner in which psychological events
contingent. Under this extinction procedure no can influence the HPA system. What is clear is that the
change in corticosterone levels occurs. psychological processes can exert profound influences
The concept of loss of control implies that there on the magnitude and direction of the responses of the
is an accompanying loss of predictability. This would HPA axis. Over the years there has been a concerted
suggest that HPA activation would also be observed effort to delineate the neurobiology of affect and
under circumstances where predictability of obtain- emotions. It should be noted that the CNS structures
ing reward is altered from high to low predictability, that have been implicated are critical in the regulation
and conversely that a shift from low to high of fear and anxiety. The amygdala and other limbic
predictability should result in a reduction of arousal system structures have been shown to be activated by
and therefore a decrease in HPA activity. Goldman the psychological stress.
et al. (1973) trained rats to bar press for water on What has been presented in this section is far from
either a continuous reinforcement or a variable an exhaustive view of the psychobiology of stress.
interval schedule. When the variable interval-trained There is an extensive literature that social isolation
rats were shifted to continuous reinforcement their can exacerbate and that social support can reduce the
corticosterone levels decreased. In contrast, when rats responses to stress (Levine, 1993). Dysregulation of
are shifted from a predictable schedule of reward to the HPA axis has been demonstrated to occur in a
a more unpredictable schedule, corticosterone levels number of mental diseases. One of the earliest
invariably elevate (Levine et al., 1972). That the HPA examples was the studies by Sachar (1980) that
axis is bidirectional has been well established. The patients with depression were hypercortisolemic.
presentation of food or water to deprived rats results Caroll et al. (1976) reported deficiencies in negative-
in a decline in the levels of ACTH and GC (Gray feedback regulation in some cases of depression using
et al., 1978; Romero et al., 1995). Perhaps even more the dexamethasone suppression test. Throughout this
impressive is that simply presenting cues signaling the paper the major focus has been on the activation of
occurrence of food and water also produce declines in the HPA axis and the factors that modulate this
circulating levels of GCs (Levine and Coover, 1976; activation. In recent years there has been an ever-
Coover et al., 1977). growing body of evidence that stress can result in a
Is there an overall set of assumptions that can persistent hypocortisolemia (Yehuda, 1998; Gunnar
account for the data just presented? Several attempts and Vazquez, 2001). The mechanisms that are
have been made to provide a theoretical basis to involved in the persistent down regulation of the
account for the activation and inhibition of the HPA HPA axis are still unknown.
 19

The neuropeptide concept neural substrates that regulates specific behaviors.

Under deWied's guidance, numerous ingenious
No discourse on the history of stress research would experiments were conducted. In his laboratory in
be even mildly comprehensive if the pioneering work Groningen they were able to successfully surgically
of David deWied were not included. I met David remove either the posterior or anterior pituitary.
when we were still young Turks trying to convince This was accomplished by a laboratory technician
the world that our then somewhat offbeat research J. Melchior. As far as I can determine he may have
findings were of some importance in the complex been the only man on earth who successfully
universe of stress, deWied and I are of the same performed this surgery. However, the ability to
generation (our birthdays are 12 days apart). isolate either lobe of the pituitary made it possible
Whereas I was engaged in research that was to examine the role of specific anterior or posterior
attempting to delineate some of the factors that pituitary hormones. He discovered that not only
determine individual differences in the HPA response, ACTH but also vasopressin had observable effects on
his mission was to show that the peptides of the learning and memory. In his laboratory in Utrecht,
pituitary were active molecules that influenced where he had assumed the professorship of pharma-
behavior not through their regulation of some remote cology in 1963, he demonstrated that the complete
hormone but acted directly on the neural substrates sequence of these peptides was not required for the
that regulate specific behavioral outcomes. His early behavioral effects to be manifested. He initiated a
work was concerned with the pituitary response to structure-activity program that eventually showed
stress. However, critical to the development of his that the complete sequence of the peptide was not
future interests was the time he spent with I. Arthur essential and that fragments of the ACTH molecule
Mirsky in Pittsburgh in 1957-1958. It was during that have profound behavioral effects in the absence of
time de Wied collaborated with R.E. Miller, an any influence on the secretion of GCs. The shortest
experimental psychologist. These studies demon- of these fragments contained only four amino acids
strated that the effects of ACTH on shuttle-box ACTH 4-7, though the most behaviorally potent
performance were not a function of the steroidogenic fragment was ACTH 4-10. I could present a litany
action of ACTH, and in fact ACTH and prednisone of experiments which were conducted not only on
had paradoxical effects in the shuttle box. That the ACTH fragments but also on fragments of vaso-
effect of ACTH was not mediated by the adrenal pressin. Over the years deWied has convincingly
cortex suggested that the brain was another target made the case for the neuropeptide concept. There is
organ for ACTH. There was emerging a body of now complete acceptance of this doctrine to the point
work around this time that suggested that ACTH where its origin has almost been forgotten. Peptides
may have behavioral effects that could be isolated derived from the gut, fat cells, pituitary, and brain
from the behavioral consequences of the GCs. Much have all been shown to exert their effects on specific
of this work came from the group of researchers behaviors, deWied's accomplishments extend well
at the University of Pecs in Hungary which included beyond the limits of this discussion. What makes him
Endroczi, Koryani, and Bohus. Bela Bohus later left an important figure in the history of stress is that
Hungary and joined with deWied's group in Utrecht. he was able to "push the envelope" and demonstrate
He went on to become a Professor at Groningen and that the so-called pituitary stress hormones can act
an influential figure in the area of stress and behavior. directly on the brain to influence behaviors relevant
Upon his return to the Netherlands, de Wied and to the stress response.
a very notable cohort of coworkers concentrated
their research efforts on demonstrating what is often
referred to as the "Neuropeptide Concept" (for a Conclusions
review, see de Wied, 1990). The grand hypothesis of
this work was that peptides emanating from the While writing this brief history of research on stress
pituitary had actions on the brain that were a I have been constantly aware of some of the
consequence of these peptides acting directly on the sage comments regarding history. Santayana wrote
20

"history is a pack of lies, about events that never craft. He commented that for him inner space was as
occurred, written by people who were never there." exciting and engrossing as outer space. I have had the
In my defense of this particular history I can say that privilege and joy of having observed and participated
the events described did happen and that I was, in in the most exciting period in the history of biology.
some instances, there when the events unfolded. I can I suspect that if I were able to see the face of
also say with pride that I was acquainted with most stress research 50 years from now it would be as
of the names that are mentioned in this chapter with unrecognizable to me as the contemporary face of
of course some notable exceptions. However, what biology would be to Charles Darwin.
is also true is that it is impossible to present an
historical account of anything that is not biased
by the historian. Thus the history of this field, as Acknowledgments
presented, is what I believe to have been the critical
milestones, the important figures, and the concepts I would like to express my appreciation to the
that altered the course of how we understand stress. National Institutes of Health, in particular N I C H D
The most glaring omission in this history is the and N I M H for the many years of support that
absence of a discussion concerning the impact of enabled me to pursue much of the research contained
molecular biology on stress research. The year 2003 in the chapter. I would like to thank Drs. F. Robert
is the 50th anniversary of the Watson and Crick's Brush, Robert Murison, and Juan Lopez for their
classic paper on the structure of DNA. Since that advice and critical comments. Finally, my deepest
time the face of biology has been dramatically gratitude to the postdoctoral fellows, graduate, and
transformed. It is difficult to communicate to the undergraduate students who made my life as a
student of today what research in biology was like scientist far more gratifying and rewarding and
without the vast array of techniques that have who contributed immeasurably to the research in
become commonplace. Much of what has been my laboratories at Stanford University and the
discovered through molecular biology was beyond University of Delaware. Many of these students are
the wildest dreams of those of us who began their now the leaders in the field.
careers prior to the molecular biology revolution.
Much of what we have learned about neural circuitry,
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This Page Intentionally Left Blank
T. Steckler, N.H. Kalin and J.M.H.M. Reul (Eds.)
Handbook of Stress and the Brain, Vol. 15
ISBN 0-444-51173-3
Copyright 2005 Elsevier B.V. All rights reserved
CHAPTER 1.2

The neuropsychology of stress

Thomas Steckler

Johnson & Johnson Pharmaceutical Research & Development, A Division of Janssen Pharmaceutica N.V.,
Turnhoutseweg 30, 2340 Beerse, Belgium

Abstract: This chapter focuses on the psychological processes which govern the stress response. After an introduction
aiming to define the terminology used in the area of stress research and some of the related concepts, such as emotions,
the stress response will be discussed within the framework of cognitive functions, including learning theory. It will be
demonstrated how situational appraisal and anticipation, predictability and controllability, and differences in coping
style will affect stress responsivity. In the final parts of the chapter, these concepts will be related to the behavioural
inhibition theory as defined by Gray and McNaughton (The Neuropsychology o f Anxiety, 2nd ed. Oxford University
Press, Oxford, 2000), and how this could be mediated by various areas in the brain.

Stressors and the stress response adrenal (HPA) axis, 1 activation of peripheral
catecholaminergic systems, and of various neuro-
Stress can be defined as any challenge to homeostasis transmitter changes in the brain. More chronically,
of an individuum that requires an adaptive response physiological stress responses can consist of the
of that individuum (Newport and Nemeroff, 2002). development of gastric ulcers, chronic changes in
Conceptually, stress consists of three components, H P A axis and neurotransmitter activity, hypertrophy
that is the input of a stimulus, the evaluation of this of the adrenal cortex, atrophy of the thymus, and loss
information, and a response output. of body weight, amongst other effects.
Aversive exteroceptive (e.g., electric shock, cold, At the behavioural level, exposure to stress
social dominance in animals, but also several has been reported to lead to a decrease in food and
psychosocial aversive situations in humans, such as water intake (Pare, 1964), to inhibit exploratory
public speech) or interoceptive (e.g., pain) stimuli are activity (Weiss et al., 1980), to suppress appetitively
referred to as stressors. A stressor can be defined as motivated responses (Annau and Kamin, 1961), to
a change in the environment that is sensed by an increase anxiety-related behaviour (File, 1980), and
organism, is aversive and potentially harmful to that to enhance or to impair both aversive and appeti-
organism and elicits acute and/or chronic responses tive learning under certain conditions (Overmier
(Ottenweller, 2000). and Seligman, 1967; Rosellini, 1978; Shors, 2001).
A stress response in turn consists of a complex
pattern of physiological, behavioural, cognitive, and/
or emotional components. Physiological processes 1One of the main players regulating HPA axis activity is
can acutely comprise of, for example, piloerection, corticotropin-releasing factor (CRF). CRF is released from the
increases in heart rate, modulation of intestinal parvocellular part of the hypothalamic paraventricular nucleus
motility, activation of the hypothalamic-pituitary- (PVN) into portal vessels, subsequently activating the HPA axis
by stimulation of release of adrenocorticotropic hormone
(ACTH) from the anterior pituitary. ACTH in turn triggers
the release of glucocorticoids (corticosterone or cortisol,
Fax: + 32 11 460 6121; E-mail: [email protected] respectively) from the adrenal cortex.

25
26

In other words, there is a prioritisation of stress functions play an important role in the processing of
responses over other types of behaviour, and the this type of stress-related information.
stressor-induced behavioural responses serve the goal However, as mentioned above, not every stressor
to reduce or eliminate the negative effects of a may involve cognitive processing and a stress
stressor. response can be induced directly by the exposure to
an aversive stimulus. This second type of stressors
has been called a physical stressor and can be defined
Types of stressors as disturbing an individual's internal milieu, leading
to activation of regulatory mechanisms that serve
A stressor can be any unpleasant intrusion to the to restore homeostasis (Kollack-Walker et al., 2000).
external or internal environment (e.g., a social Such stressors would include, for example, starva-
encounter, noise, an electric footshock, exposure tion, noise, cold exposure, or haemorrhage.
to extreme temperatures, or an infection), or a with- Besides covering different baskets with stressors,
drawal from the environment (e.g., starvation, social which involve cognitive processes to different degrees,
isolation, or separation of an infant from its mother). the distinction between psychological and physical
The stressor can be presented once only for a short stressors gains relevance by the finding that these two
time (e.g., administration of a single footshock of a types of stressors seem to activate different parts of
few milliseconds duration), for longer times (e.g., the brain. Physical stress seems to be relayed directly
exposure to cold temperatures for several hours), to the PVN of the hypothalamus, part of the
repeatedly (e.g., exposure to a series of repeated HPA axis, by ascending viscero- and somatosensory
footshocks spaced over time, or repeated social defeat pathways (Sawchenko and Swanson, 1983; Kovacs
by a dominant subject, with the two subjects being and Makara, 1990; Sawchenko et al., 1996), rather
fully separated in-between), or chronically/enduring than to higher brain areas. Psychological stress, on
(e.g., exposure to cold temperatures over days, or the other hand, seems to involve a number of higher
constant exposure of a defeated subject to the brain areas, including various neocortical areas, the
dominant subject). Moreover, some internal stimuli, hippocampus, and the septal complex, presumably
such as anxiety and fear, can constitute a component because it needs to be identified and evaluated first,
of a stressor (e.g., in case of a patient suffering from and the PVN serves as relay point between the higher
an anxiety disorder) but, as will be discussed below, brain areas and the HPA axis.
can also be part of a stress response (Young and What exactly constitutes a physical stressor
Liberzon, 2002). rather than a psychological stressor can, however,
A stress response (e.g., an increase in HPA-axis sometimes be a matter of debate. Although Kollack-
activity) can be induced in a relatively simple, reflex- Walker and colleagues (2000) provide a clear defini-
like manner, in which case it does not necessarily tion, which unambiguously distinguishes between
require an evaluation of the situation by the subject. stressors based on their primary location, i.e.,
Alternatively, a stress response can also entail inputs whether they originate internally or externally of the
from higher brain areas, i.e., a stress response can subject, it is obvious that most stressors must be seen
involve the evaluation of the stressor as being as compound stressors, affecting the subject both
stressful. In particular, so-called psychological stress from its external and internal milieu. Swim stress, for
(for example, novelty stress and social defeat) has example, includes both an external component (e.g.,
been suggested to activate these higher systems a situation where the subject faces the threat of
(Herman et al., 1996; Herman and Cullinan, 1997). drowning) and an internal component (e.g., hypo-
Psychological stress can be defined as involving thermia due to swimming in cold water). Therefore,
a reaction to an aversive stimulus in an individual's it could be argued that it may be more appropriate
external environment (Kollack-Walker et al., 2000), to see the two definitions of physical and psycholog-
and has been viewed as an asymmetry between the ical stressors as two extremes of a continuous scale,
motivational systems of reward and punishment with most stressors laying in-between. According
(Walker, 1987). This already implies that cognitive to this view, it is the relative balance between
 27

psychological and physical components that varies and the body, i.e., considered emotions to consist of
between stressors. Indeed, some stressors, originally behavioural, autonomic, and endocrine responses,
considered as physical stressors (e.g., swim stress), which can differ according to the nature of the
are now increasingly considered psychological stress. emotion. For example, there is evidence that negative
Thus, there is some intuitive blurring of the dicho- emotions increase heart rate and change skin
tomy and there appears to be a gradual difference temperature more than pleasant emotions (Ekman
rather than an absolute distinction. On the functional et al., 1983). Behaviourally, emotions can be viewed
neuroanatomical level, however, it becomes increas- as central states elicited by reinforcing stimuli
ingly clear that different stressors activate different (Plutchik, 1967). Especially secondary punishing
pathways, and it has been suggested that one way stimuli have been associated with negative emotions
to distinguish between psychological and physical such as fear (Mowrer, 1960), which can be viewed as
stressors is by directly looking at the pathways a state anticipating primary punishment. Rolls (1999)
activated by these stressors, i.e., the brain itself would defined emotions as 'a state elicited by rewards or
be the best tool to categorise complex stressors punishers, leading to changes in rewards or punish-
(Dayas et aI., 2001). ers' (p. 60). He considers emotions as a cognitive
Inherent to the concept of psychological and process which results in a decoded signal that an
physical stressors is the fact that the subject is environmental event (at the time of presentation or as
exposed to (external or internal) aversive stimuli. a remembrance) is reinforcing or punishing, together
To fully appreciate the role of stress systems, it is with the affective state produced as a result. Within
however important to realise that not only aversive that definition, an affective state differs from an
stimuli, but also reinforcement and withdrawal from emotion in that the former on its own lacks an
an appetitive situation affect the activity of the external sensory input and the cognitive decoding,
HPA axis (withdrawal from reward may of course be i.e., there is no present or past environmental event
considered as representing an aversive stimulus in towards which the affective state is directed, which
its own right). Thus, reinforcement has been shown would then lead to a goal-directed behaviour (Rolls,
to decrease plasma corticosterone level in rats trained 1999).
on an operant task, while extinction, i.e., operant It is clear from these definitions that emotions
responding followed by withdrawal of the expected form an integral part of the response to a
reward, increases plasma corticosterone level (Coe (psychological) stressor. Functionally, it has been
et al., 1983; De Boer et al., 1990). suggested that the emotional responses are of rele-
In the following parts of this chapter, I will focus vance for coping reactions to short-term aversive
on the processes which take place during the events (a topic which will be covered in more detail
evaluation of the information provided by a stressor. below) and for the initiation of fight-flight-freezing
Before going into further detail, it is however reactions, which serve the subject to deal effectively
important to first clarify a concept central to this with a source of danger and to return into a state
discussion, that is the question of what is meant when of safety. Interestingly, there seems to be a more
talking about an emotion. rapid target detection for emotional stimuli such as
fear-related (but also positive emotional) stimuli
in humans (Ohman et al., 2001), and such target
Emotions related to stress exposure stimuli seem to be processed even though the stimuli
are not perceived, as can be evidenced by alterations
The stress-induced behavioural changes mentioned in skin conductance responses (Esteves et al., 1994),
above can be, but do not have to be, part of what i.e., these emotionally relevant stimuli will even be
is considered an emotional response. James (1890) detected under conditions of limited attentional
suggested that emotion-provoking stimuli induce resources (pre-attentive processing), which makes
bodily changes, and that the feeling of these changes sense in that those stimuli to which a value has been
would be the emotion. Others extended this view and ascribed, e.g., a stressor, will be of high relevance
associated emotions with changes in the brain to the individuum.
28

The stress r e s p o n s e - a cognitive view paradigm, and Roman Low Avoidance rats were
faster than Roman High Avoidance rats (Koene and
It is obvious from the points raised above that Vossen, 1991). In a runway situation, Wistar Kyoto
cognitive processes play an important role for the rats were faster in solving a conflict than randomly
adequate reaction to stress exposure. The importance bred Wistar Wu rats and Brown Norway rats were
of such processes appears evident by the simple faster than Wistar Wu rats (Koene and Vossen, 1991).
notion that subjects should learn to repeat responses The value of the defensive distance is composed
that lead to reward or prevent punishment, and of the objective physical or temporal distance
should learn to inhibit responses that prevent or between subject and stressor, and the subjective
truncate rewards or lead to punishment, i.e., it is assessment of threat originating from the stressor
learned that the appropriate action should prevent (Blanchard and Blanchard, 1990). This in turn
the (re-)occurrence of a certain stressor. As an implies that in the absence of a stressor, there should
extreme example, a subject should remember the be no behavioural inhibition. In the presence of a
appearance, smell, sound, and environmental loca- moderate stressor, there may be behavioural inhibi-
tion of a predator to predict its next occurrence to tion of non-defensive behaviour (e.g., a decrease in
maximize the likelihood for survival. Under daily food and water intake, inhibition of exploratory
laboratory conditions, a rat will use related informa- activity, and suppression of appetitively motivated
tion about its cage mates to adhere to hierarchical responses), but not of defensive behaviour (fight or
orders for food and water access. flight; risk assessment), while under conditions of
This concept is not new, but the relevance of high stress, both defensive and non-defensive types of
cognitive processes for the response to a stressor behaviour would be inhibited (freezing).
has been noted as early as 1926 by Freud in the In this respect, it is interesting to note that
psychoanalytical theory of defence mechanisms, Takahashi (1996) suggested that glucocorticoids,
suggesting that denial and intellectualisation are which are released under stressful conditions, may
fundamental ways to reduce anxiety. Thus, changes also influence freezing during development by actions
in cognitive function can result in changes in the at the septohippocampal level, thereby modulating
way a stressor is perceived, remembered, or how a the individual's levels of stress-induced arousal and
stressful situation is solved. attention to threat. This is an interesting idea in the
context of Gray's theory on behavioural inhibition,
which will be discussed below.
The concept of defensive distance

In order to cope with a stressful situation, a subject can Appraisal and anticipation
have two major strategies: it can try to avoid
the stressor (defensive avoidance) or to approach the In order to choose between approach and avoidance
stressor (defensive approach), the latter of which most effectively, the subject must be able to appraise
includes risk assessment and behavioural inhibition. It the situation it has to deal with. The concept of
has been proposed that the relative importance of the defensive distance suggests that the subject is able to
two competing types of behaviour (avoidance appraise its position relative to the stressor, i.e., there
and approach) will depend on the so-called defensive is a quantitative aspect. However, a subject must also
distance between the subject and the stressor be able to appraise a stressor in a qualitative way, i.e.,
(Blanchard and Blanchard, 1990). Moreover, the whether a given stimulus is a severe stressor, a mild
speed with which such conflict can be resolved in an stressor, or no stressor at all. In 1968, Mason
approach-avoidance situation seems to be related to suggested that the appraisal of a stimulus determines
genetic factors and underlying stress responsivity. For whether it is perceived as a stressor, i.e., that the
example, Tryon Maze Bright rats have been reported subject must discriminate between threatening and
to be faster in speed of conflict resolution than Tryon non-threatening situations. In other words, the
Maze Dull rats in an operant-conditioned punishment meaning of a stimulus is, at least in part, determined
 29

by the representations held by the subject, which can integral part of some definitions of stress. Lazarus
be innate or acquired. This can be exemplified by the (1966), for example, conceptualised stress as the
condition of novelty stress. Exposure to novelty alters interaction between the demands of the situation and
both HPA axis and behavioural activities (Lemaire the individuals ability to cope. Hence, coping is an
et al., 1999; Hall et al., 2000). Novelty, however, active response to resolve a stressful situation. It
is not an inherent characteristic of a stimulus, but an encompasses cognitive and other behavioural efforts
attribution given to the stimulus by the subject. to reduce or adapt to a stressor.
In addition to the appraisal of a situation, it is In principle, a subject can appraise two compo-
important to acknowledge that a subject's responses nents of a situation: First, it can assess whether a
are not only driven by reactive demands, but also situation is irrelevant, appetitive, or aversive, as
by anticipation. Arthur (1987), for example, demon- was discussed above (so-called primary appraisals).
strated that anticipation of an aversive stimulus, such Secondly, it can make an assessment of the relevance
as an electric shock, may result in an even greater and availability of its own coping strategies (so-called
stress response in rats (as measured in activation of secondary appraisals). The success of a given coping
the HPA-axis) than confrontation with the aversive strategy is situation specific and its appropriateness
stimulus itself. Similar findings were reported by will, at least in part, depend on defensive distance,
others and extended to other measures, including as the defensive distance will determine whether
anticipatory changes in pain threshold (Przewlocka approach or avoidance are more likely to be
et al., 1990; Yamamotova et al., 2000). Likewise, successful.
anticipatory stress responses can be observed in Differences in stress coping have been implicated
humans, for example, when facing a public speech, in stress resiliance and hence different vulnerability
and this stress response can be altered by manipula- to psychiatric disease. The constitutional vulnerabil-
tion of cognitive processes (Rohrmann et al., 1999): ity of individuals to stress is named diathesis. As
the degree to which individuals are stressed anticipat- already mentioned, such individual differences are
ing public speech (as measured by HPA-axis based on genetic factors, physiological developmental
activation, changes in heart rate, subjective arousal, factors, and lifetime experience. We have already seen
and state anxiety) depends on manipulative feedback that different strains of rats exhibit different speeds of
(reassuring or arousing) given during that period conflict resolution. Another example derives from the
(Rohrmann et al., 1999), but also on the level of simple reaction to novelty, which has been shown to
control that subjects experience over the situation differ between inbred strains of rats, suggesting a
(see below). genetic base (Gilad and Shiller, 1989).
Conversely, differences in reaction to novelty can
also be observed within a population of rats (Lemaire
Stress coping et al., 1999; Piazza et al., 1991), suggesting epigenetic
factors also play a role. The importance of epi-
It is evident that cognitive appraisal of a situation genetic factors is also illustrated by the findings
will determine the strategy chosen by an individual to that prenatally stressed animals are more impaired in
deal with, or to cope with a stressor. In this context, coping with stress compared to non-stressed controls
it is common knowledge derived from everyday (Weinstock, 1997), and that rat pups, which differ
experience, but also from sophisticated and well- in the level of maternal care (maternal licking and
controlled studies, that there are very clear individual grooming) while being nursed, will show differences
differences in stress coping. As already pointed out, in the response to novelty stress later in life (Liu
these differences between individuals seem to be in et al., 1997). Interestingly, these high- and low-
part based on genetic factors (Koene and Vossen, reacting rats do not only differ in behavioural and
1991), which interact with developmental and neuroendocrine measures, but also in neuroanatomi-
situational influences (see below). cal features, and show a reduced neurogenesis
The importance of the concept of coping is in the dentate gyrus of the hippocampus (Lemaire
highlighted by the fact that the ability to cope is the et al., 1999).
30

As an interim summary, we can conclude so far in stressful environments. In escape learning, the
that different stressors will lead to different patterns aversive stimulus occurs conspicuously before each
of brain activation. Some, but not all, stressors will response, while in avoidance learning, the stressor,
involve a cognitive component, including appraisal if learning is successful, is rarely, if ever, seen. These
and anticipation of a situation, leading to an avoidance responses can be very persistent under
emotional response and a variety of different coping conditions of extinction, i.e., in the absence of
strategies, which are under control of genetic and the primary stressor, and well-learned avoidance
epigenetic factors. From that, it can easily be seen responses may be sustained for some time purely as
that behavioural and affective changes can even an automatic habit (Mackintosh, 1983). By analogy,
precede the presentation of a primary stressor and presentation of a secondary stressor, followed by
are under control of the laws of classical- and presentation of a primary stressor and escape, is
operant-conditioning processes, where stimuli pre- likely to generate anxiety, while absence of the
sented to the subject have been associated with the primary stressor due to avoidance after presentation
stressor before. of the secondary stressor, should result in diminished
anxiety and merely lead to a habitual response.
It is of course also possible to extinguish an
Learning processes modulating avoidance response. Interestingly, extinction of avoid-
s t r e s s responsivity ance learning has been suggested to be under control
of the activity of the HPA axis. More specifically,
Next, the role of learning processes in the modulation extinction of passive avoidance has been suggested to
of stress responsivity will be discussed in more be modulated via activation of the mineralocorticoid
detail. Associating a given stimulus with a stressor is receptor (MR), while extinction of active avoidance
equivalent to meaning that a certain stimulus will has been suggested to be modulated via activation of
have acquired the qualities of a secondary stressor (or the glucocorticoid receptor (GR) 2 (Korte, 2001).
a conditioned stimulus). Once the subject has made Such learned responses can be assessed in the
such an association, it can respond in a way to the animal in procedures such as conditioned suppres-
aversive situation similar to a response that has led to sion or conflict procedures, conditioned emo-
a successful outcome in the past, i.e., it can elicit a tional response (CER), or fear-potentiated startle.
prepared response (Phillips, 1989). Conditioned suppression or conflict procedures entail
One model which would allow a subject to predict the suppression of a consummatory or exploratory
the occurrence of a stressor would be related to behaviour in the presence of a stimulus (the
classical conditioning procedures, whereby the sub- conditioned stimulus) previously associated with an
ject has to associate the stressor with a discrete cue, aversive stimulus (the unconditioned stimulus) and
which could be simple (such as a tone or a light) or could, for example, involve the suppression of a lick
complex (such as the environmental context in which for water or a freezing response (the latter being
this stressor appears). Such classical conditioning mediated by the periaqueductal grey; Graeff, 1994).
procedures are frequently used in animals and have These behavioural responses can occur within parts
also been reported in humans (Watson and Rayner, of a second, faster than any neuroendocrine changes,
1920). The conditional stimulus in turn can be but are still under neuroendocrine control. The
associated with an emotional tone, such as fear. freezing response, for example, already takes place
Alternatively, the subject could learn an instru-
mental or so-called operant response, i.e., the subject
acquires a behavioural pattern that has the capacity 2Two corticosteroid receptors have been identified in the brain,
to alter the frequency of the subject's exposure to the MR and the GR, which differ in expression patterns and
binding properties (GR binds corticosteroids with a 10-fold
certain events.
lower affinity than MRs). It has been suggested that MRs are
Within this framework, two types of learning involved in the maintenance of the activity of the stress system,
have been distinguished, namely escape and avoidance while GRs, in conjunction with MRs, may mediate the recovery
learning, essential forms of behavioural reactions from stress (Reul and De Kloet, 1985; De Kloet et al., 1998).
 31

before activation of the HPA axis, but has been et al., 1977). Thus, our stress systems are capable
suggested to be acutely modulated by M R activation of learning and we can a d a p t - or m a l a d a p t - to a
(Korte, 2001). Korte argues further that the first stressful situation, with all the consequences asso-
reaction of an animal (such as a rat or a mouse) ciated with stress-related psychiatric disorders.
visiting a dangerous location for which an aversive In the context of learning theory, adaptation and
memory has been formed will be conditioned freezing maladaptation are better referred to as habituation
behaviour, modulated by a permissive role of the and sensitization. Habituation, an active-learning
MR. Although it is evident thatthe other factors will process not to respond to irrelevant situations,
contribute to such response as well, this example governs the decline of the stress response when the
again nicely illustrates the interrelationship between subject is repeatedly exposed to the stressor. During
behavioural processes and stress systems, which goes habituation, the orienting response towards the
both ways. If the environment turns out to be safe, stressor is diminished. This can be seen, for example,
extinction of passive and active avoidance will take by the fact that a novel stimulus, which induces
place. a stress response upon initial exposure, becomes
In contrast, a CER often involves suppression a habituated stimulus after repeated exposure.
of an instrumental response, for example, of lever Behaviourally, such stimulus will elicit exploration,
pressing for food, upon presentation of an aversive which is reduced upon repeated exposure.
CS. In fear-potentiated startle (mediated by the Sensitization refers to an exaggeration of the stress
pontine reticular nucleus; Davis, 1992b), the magni- response and is seen, for example, if animals are
tude of the startle response is increased in the exposed to a mild stressor (e.g., a novel stimulus)
presence of an aversive CS, the state retrieved by the after exposure to a strong aversive stimulus. Rats
CS is fear. Fear-potentiated startle has been pre-exposed to inescapable footshock, for example,
suggested to be a sensitive measure of anticipatory have been demonstrated to display progressive and
anxiety (Davis et al., 1993). long-lasting increases in anxiety-related behaviour
The examples given above highlight the impor- (Van Dijken et al., 1992), and to develop autonomic
tance of first-order conditioning processes in the (Bruijnzeel et al., 2001) and neuroendocrine changes
response of a subject to a stressor, but this can of (Van Dijken et al., 1993), which last for weeks.
course also be extended to second-order condition- Likewise, social defeat of one rat by another rat
ing. For example, a rat might have learned to stop can induce long-lasting behavioural changes in the
responding in the presence of a CS (e.g., a light) in a defeated animal, such as an increase in immobility
conditioned suppression paradigm in the absence of (Koolhaas et al., 1990). During this stage, the
an UCS. If the CS is now preceded by another neutral orienting response towards the stressor would be
stimulus (e.g., a tone), the presentation of the second enhanced.
stimulus can eventually also lead to suppression of At the neuroendocrine level, it has been shown
the ongoing behaviour after a few pairings. The that a single exposure to electric footshock can
relevance of second-order conditioning lays in the induce vasopressin (AVP) levels in corticotropin-
fact that it helps to explain how anxiety can releasing factor (CRF) terminals in the median
generalise from one anxiogenic event to a number eminence for at least 11 days (Schmidt et al., 1996),
of other, more or less closely related, originally and it has been suggested that the sensitized response
neutral stimuli. is due to enhanced AVP release, which potentiates
However, conditioning is not restricted to behav- the effect of CRF on ACTH release (Van Dijken et al.,
ioural responses, but extends to autonomic and 1993).
neuroendocrine functions as well. For example, it has Sensitization has also been reported in humans,
been shown that increases in plasma corticosterone leading to greater hormonal stress response over time
levels can be conditioned to stimuli associated with a and an increase in baseline cortisol levels (Young
poison (Adler, 1976). Conversely, decreases in plasma and Akil, 1985; Dallman, 1993). Moreover, it has
corticosterone levels have been conditioned to stimuli been shown that pre-exposure to stress sensitizes
associated with daily feeding and drinking (Coover the release of noradrenaline at various brain levels
Another random document with
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pretty abundantly with foliage; the foot-stalks of the old leaves becoming
cirrhi or tendrils, and the wood growing to a considerable thickness. The
flowers begin to appear about May; and continue in succession, till July. It
may be propagated by layers; but, the surest mode is by seed, which may be
sown as soon as ripe, and which will be perfected from the first flowers, by
August. It grows the most flourishing in light rich earth; but will live in the
most common. Our figure was made from a plant in the Hammersmith
collection, to which it was first introduced in the year 1792.
 PLATE CLXXXI.

VACCINIUM VIRGATUM.

Green-twigged Whortle-berry.

CLASS VIII. ORDER I.

OCTANDRIA MONOGYNIA. Eight Chives. One Pointal.

ESSENTIAL GENERIC CHARACTER.

Calyx superus. Corolla monopetala. Filamenta receptaculo inserta. Bacca

quadrilocularis, polysperma.
Cup superior. Blossom one petal. Threads fixed into the receptacle. A
berry with four cells and many seeds.
See Vaccinium Arctostaphyllos. Pl. XXX. Vol. I.

SPECIFIC CHARACTER.

Vaccinium foliis oblongo-ovatis, ferrulatis, deciduis, ramulis viridibus;

floribus, sub-umbellatis, axillaribus; corollis, sub-cylindraceis; calycibus
apice reflexis. Staminibus decem.
Whortle-berry with oblong egg-shaped leaves, slightly sawed, deciduous,
the small branches green; flowers grow rather umbelled from where the
leaves are fixed to the stem; blossoms nearly cylindrical; cups reflexed at the
upper part. Ten chives.

REFERENCE TO THE PLATE.

1. A flower complete.
2. The Cup.
3. The Chives, Pointal, and Seed-bud, the cup cut off, magnified.
4. A nearly ripe berry.
This species of Whortle-berry was, according to the Kew Catalogue,
introduced by Mr. Young in the year 1770. It is a hardy plant; and, as a
native of North America, where it is an under shrub of the woods, should be
planted in a shady situation, in peat earth. It is rarely killed by our frosts;
grows about two feet high, and loses its leaves in winter. Our drawing was
made in June, this year, at the Nursery, Hammersmith, where it is propagated
by layers.
 PLATE CLXXXII.

MALVA DIVARICATA.

Straddling-branched Mallow.

CLASS XVI. ORDER VI.

MONADELPHIA POLYANDRIA. Threads united. Many Chives.

ESSENTIAL GENERIC CHARACTER.

Calyx duplex; exterior 3-phyllus. Arilli plurimi, monospermi.

Cup double; outer three-leaved. Seed-coats many, one-seeded.
See Malva reflexa, Pl. CXXXV. Vol. II.

SPECIFIC CHARACTER.

Malva foliis lobatis, plicatis, dentatis, scabridis; ramis ramulisque

divaricatis, flexuosis.
Mallow with lobed leaves, plaited, toothed, and rough; the large and
small branches grow straddling, and zig-zagged.

REFERENCE TO THE PLATE.

1. The double Cup.

2. A Flower spread open, with the threads remaining.
3. The Chives cut open, and magnified.
4. The Seed-bud, Shaft, and Summits, magnified.
As a lively, but little, green-house plant, this species of Mallow has not
many equals; and its property of continuing to flower from June, till
December, must considerably enhance its value. It is a native of the Cape of
Good Hope, and was introduced to us, about four years since. Most
collections now possess it, from its facility of increase, may be planted in
rich earth, and is increased by cuttings, or seeds, which ripen perfectly in this
country. The drawing was made at the Nursery, Hammersmith.