Handbook of Stress and the Brain Part 2: Stress: Integrative and Clinical Aspects

456 Pages·2005·45.526 MB·English

by  Reul, J. M. H. M., Kalin, N. H., Steckler, T

List of Contributors, Part 2
J.S. Andrews, Ascend Pharmaceutical Inc., Speakman Drive, Mississauga, ON, Canada
M. Bonacina, Department of Internal Medicine and Medical Therapy, University of Pavia,
Piazza Borromeo ,2 271000 Pavia, Italy
.T Cartmell, National Institute for Biological Standards and Control (NIBSC), Blanche
Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, UK
A.R. Cools, Department of Psychoneuropharmacology, P.O. xoB 9101, 6500 HB Nijmegen,
The Netherlands
S.C. Coste, Department of Molecular Microbiology and Immunology, L220, Oregon Health
and Science University, 3181 WS Sam Jackson Park Road, Portland, OR ,8903-93279
USA
L. Cravello, Department of Internal Medicine and Medical Therapy, University of Pavia,
Piazza Borromeo ,2 271000 Pavia, Italy
A.C. Dettling, Swiss Federal Institute of Technology Zurich, Schorenstrasse ,61 CH-8603
Schwerzenbach, Switzerland
A.Y. Deutch, Vanderbilt University School of Medicine, Psychiatric Hospital at Vanderbilt,
Suite 313, 1061 23rd Avenue South, Nashville, TN 37218, USA
A.J. Dunn, Department of Pharmacology and Therapeutics, Louisiana State University
Health Sciences Center, P.O. xoB 33932, Shreveport, LA ,2393-03117 USA
B.A. Ellenbroek, Department of Psychoneuropharmacology, P.O. xoB 9101, 6500 HB
Nijmegen, The Netherlands
J. Feldon, Swiss Federal Institute of Technology Zurich, Schorenstrasse ,61 CH-8603
Schwerzenbach, Switzerland
E. Ferrari, Department of Internal Medicine and Medical Therapy, University of Pavia,
Piazza Borromeo ,2 271000 Pavia, Italy
E.J. Geven, Department of Psychoneuropharmacology, P.O. xoB 9101, 6500 HB Nijmegen,
The Netherlands
.G Griebel, CNS Research Department, Sanofi-Synthelabo, 13 Avenue Paul Vaillant-
Couturier, 92220 Bagneux, France
A.C. Grobin, Department of Psychiatry CB#7160, UNC-Chapel Hill School of Medicine,
1007 Neurosciences Hospital, Chapel Hill, NC 27599, USA
L. Groenink, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht,
Utrecht, The Netherlands
.F Holsboer, Max Planck Institute of Psychiatry, Kraepelinstrase 2-10, 80804 Munich,
Germany
S. Khan, Department of Psychiatry, University of Michigan, VA Medical Center Research
(11R), 2215 Fuller Road, Ann Arbor, MI 48105, USA
S. Levine, Department of Psychiatry, Center for Neuroscience, University of California at
Davis, Davis, CA 95616, USA
R.R.J. Lewine, Department of Psychological and Brain Sciences, University of Louisville,
Louisville, KY 40292, USA
L Liberzon, Department of Psychiatry, University of Michigan, 1500 E Medical Ctr Dr
UH-9D, Box 0118, Ann Arbor, MI 48109, USA
J.A. Lieberman, UNC Chapel Hill School of Medicine, CB#7160, 7025 Neurosciences
Hospital, Chapel Hill, NC 27599, USA
L. Lu, Behavioral Neuroscience Branch, IRP/NIDA/NIH, 5500 Nathan Shock Drive,
Baltimore, MD 21224, USA
.F Magri, Department of Internal Medicine and Medical Therapy, University of Pavia,
Piazza Borromeo ,2 271000 Pavia, Italy
M. Marinelli, INSERM U-588, Universit6 de Bordeaux ,2 Rue Camille Saint-SaEns,
33077 Bordeaux Cedex, France
C.E. Marx, Duke University School of Medicine, Durham VA Medical Center, Mental
Health Service line 116A, 805 Fulton Street, Durham, NC 27705, USA
D. Mitchell, Brain Function Research Unit, School of Physiology, University of
Witwatersrand Medical School, York Road, Parktown 2193, Johannesburg, South Africa
S. Modell, Neuroscience, Bristol-Myers-Squibb, Sapporobogen 5-8, D-80809 Munich,
Germany
S.E. Murray, Department of Molecular Microbiology and Immunology, L220, Oregon
Health and Science University, 3181 WS Sam Jackson Park Road, Portland, OR 97239-
3098, USA
B. Olivier, Department of Psychopharmacology, Utrecht Institute of Pharmaceutical
Sciences, Faculty of Pharmaceutical Sciences, Utrecht University, Sorbonnelaan ,61
3584 CA Utrecht, The Netherlands
R. Oosting, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht,
Utrecht, The Netherlands
P.V. Piazza, INSERM U-588, Universit6 de Bordeaux ,2 Institut Frangois Magendie, 1 Rue
Camille Saint-SaEns, 33077 Bordeaux Cedex, France
C.R. Pryce, Behavioural Neurobiology Laboratory, Swiss Federal Institute of Technology
Zurich, Schorenstrasse ,61 CH-8603 Schwerzenbach, Switzerland
J.M.H.M. Reul, Henry Wellcome Laboratories for Integrative Neuroscience and
Endocrinology, The Dorothy Hodgkin Building, University of Bristol, Whitson Street,
Bristol, 1SB 3NY, UK
N.M.J. Rupniak, Clinical Neuroscience, Merck Research Laboratories, BL2-5, West Point,
PA 19486, USA
D. Rfiedi-Bettschen, Swiss Federal Institute of Technology Zurich, Schorenstrasse ,61
CH-8603 Schwerzenbach, Switzerland
R.R. Sakai, Department of Psychiatry, University of Cincinnati Medical Center, 2170
E. Galbraith Road, Bldg. 43/UC-E, Cincinnati, OH, USA
.F Salmoiraghi, Department of Internal Medicine and Medical Therapy, University of Pavia,
Piazza Borromeo ,2 271000 Pavia, Italy
.C Serradeil-Le Gal, Sanofi-Synthelabo Recherche, Toulouse, France
.Y Shaham, Behavioral Neuroscience Branch, IRP/NIDA/NIH, 5500 Nathan Shock Drive,
Baltimore, MD 21224, USA
R. Sinha, Department of Psychiatry, Yale University School of Medicine, 43 Park Street,
Room S110, New Haven, CT 06519, USA
LE.M. Stec, Institute of Pathophysiology, University of Innsbruck, Medical School,
Fritz-Pregl-Str. 3/IV, A-6020 Innsbruck, Austria
iiv
.T Steckler, Johnson & Johnson Pharmaceutical Research & Development, A Division of
Janssen Pharmaceutica N.V., Turnhoutseweg ,03 2340 Beerse, Belgium
M.P. Stenzel-Poore, Department of Molecular Microbiology and Immunology, L220,
Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland,
OR 97239-3098, USA
P. Sterzer, Department of Neurology, Johan Wolfgang Goethe-University, Theodor-Stern-
kai ,7 D-60590 Frankfurt am Main, Germany
K.L.K. Tamashiro, Department of Psychiatry, University of Cincinnati Medical Center,
2170 E. Galbraith Road, Bldg. 43/UC-E, Cincinnati, OH, USA
M. naV Bogaert, Department of Psychopharmacology, Utrecht Institute of Pharmaceutical
Sciences, Faculty of Pharmaceutical Sciences, Utrecht University, Sorbonnelaan ,61 3584
CA Utrecht, The Netherlands
R. naV Oorschot, Rudolf Magnus Institute of Neuroscience, University Medical Centre
Utrecht, Utrecht, The Netherlands
D.M. V~zquez, University of Michigan, 1150 Medical Center Drive, Ann Arbor, MI 48109-
9550, USA
G.J. Wiegers, Institute of Pathophysiology, University of Innsbruck, Medical School, Fritz-
Pregl-Str. 3/IV, A-6020 Innsbruck, Austria
R. Yehuda, Psychiatry Department and Division of Traumatic Stress Studies, Mount Sinai
School of Medicine and Bronx Veterans Affairs, Bronx, NY, USA
E.A. Young, Department of Psychiatry and Mental Health Research Institute, 502 Zina
Pitcher Place, University of Michigan, Ann Arbor, MI 48109, USA
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 DNA 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 2, treats the complexity of short-term and long-term regulation of stress
responsivity, the role of stress in psychiatric disorders as based on both preclinical and
clinical evidence, and the current status with regard to new therapeutic strategies targeting
stress-related disorders.
Thomas Steckler
Ned Kalin
Hans Reul
.T Steckler, N.H. Kalin and J.M.H.M. Reul (Eds.)
Handbook of Stress and eht Brain, Vol. 51
ISBN 1-32815-444-0
Copyright 2005 Elsevier B.V. llA rights reserved
CHAPTER 1.1
Hypothalamic-pituitary-adrenal axis
in postnatal life
Delia M. Vfizquez *'~ and Seymour Levine 2
tnemtrapeD1 of Pediatrics, University of Michigan, 1150 Medical Center Drive, Ann Arbor, MI 48109-9550, USA;
retneC2 for Neuroscience, Department of Psychiatry, University of California, Davis, Davis, California, 95616, USA
:yrassolG Maternal deprivation: separation of mother and infant during the stress-hyporesponsive period, which needs
to last for at least 8 h for immediate and persistent effects on the neuroendocrine regulation of the hypothalamic-
pituitary-adrenal axis.
Stress-hyporesponsive period: a period of reduced adrenal corticosterone and pituitary adrenocorticotrophic hormone
release in response to stress lasting in the rat from postnatal days 4-14.
Based primarily on the pioneering work of the late Hans Selye, the stress response has become somewhat synonymous
with the release of hormones from the pituitary and adrenal glands. Thus, in most adult mammals stimuli presumed
to be stressful result in a systematic release of adrenocorticotrophic hormone (ACTH) and the subsequent secretion
of glucocorticoids from the adrenal. This simplistic view of the pituitary-adrenal axis as first described by Selye has
been elaborated on extensively. Thus, the regulation of the so-called stress hormone clearly involves specific peptides
synthesized and stored in the brain (i.e., corticotropin-releasing factor ((CRF) and arginine vasopressin (AVP)) and
brain-derived neurotransmitters (i.e., noradrenaline). Thus the brain must be included as a critical stress-responsive
system. However, the sequence of responses observed consistently in the adult are in many ways very different in the
developing organism. Abundant evidence indicate that the rules that govern the activity of the hypothalamic-pituitary-
adrenal (HPA) axis in the adult are very different in the neonate. This is best appreciated in rodent. Thus, in this
chapter, the ontogeny and regulation of the rodent HPA is discussed. In addition, developmental aspects of the human
HPA axis during the first years of life are reviewed.
Stress-hyporesponsive period (SNRP) (Shapiro et al., 1962). It is important to note
that for the most part the basis for this description
In 1950, a report appeared that first indicated that was the inability of the rat pup to show significant
the neonatal response to stress deviated markedly elevations of corticosterone (CORT) following stress.
from that observed in the adult rodents and thus, There was one study that received little attention at
created a field of inquiry that has persisted for over the time but did raise important questions concern-
four decades. Using depletion of adrenal ascorbic ing the validity of the notion of an SNRP. In that
acid as the indicator of the stress response, Jailer study, in addition to exposing the pup to stress and
reported that the neonate did not show any response demonstrating a lack of CORT response, another
to stress (Jailer, 1950). By the early 1960s, Shapiro group was injected with adrenocorticoid hormone
placed a formal label on this phenomenon and (ACTH) (Levine et al., 1967). These pups also failed
designated it as the "stress nonresponsive period" to elicit a CORT response, which indicated that one
of the factors contributing to the SNRP could be
a decreased sensitivity of the adrenal to ACTH.
*Corresponding author: E-mail: [email protected]
Therefore, it was conceivable that other components can at times exceed 05 ~tg/dl, rarely does the infant
of the HPA axis might be responsive to stress. The reach levels that exceed 01 ~tg/dl during the SHRP.
resolution of this question was dependent on the These levels are reached only under special cir-
availability of relatively easy and inexpensive proce- cumstances, which shall be described later. Thus,
dures for examining other components of the the ability of the neonatal adrenal to secrete CORT
HPA axis. The methodological break-through, which seems to be impaired markedly. Morphological,
altered most of the endocrinology and had a major biochemical, and molecular biological studies suggest
impact on our understanding the ontogeny of the that the development of the adrenal cortex is in part
stress response, was the development of radio- responsible for this phenomenon. Chromaffin cells in
immuneassay (RIA) procedures. the adrenal medulla and maternal factors are also
The initial impact of the RIA was to change important (see Section "Adrenal Sensitivity").
the designation of this developmental period from The mature adrenal cortex in the rodent consists
the SNRP to the "stress-hyporesponsive period" of three concentric steroidogenic zones that are
(SHRP). This change was a result of studies that morphologically and functionally distinct: the zona
showed a small but significant rise in CORT when glomerulosa (ZG), the zona intermedia, and the zona
measured by RIA (Sapolsky and Meaney, 1986). fasciculata (ZF)/reticularis (ZR). The ZG, ZF/ZR
Although the response of the adrenal was reduced have unique expression of specific steroidogenic
markedly during the SHRP, the adrenal si capable of enzymes that defines the specific steroid produced
releasing small amounts of CORT when exposed to by each zone (Parker et al., 2001). Thus, cytochrome
certain types of stress. P450 aldosterone synthase (P450aldo) is produced
When investigators began to examine other com- within the glomerulosa to produce the mineralocor-
ponents of the neonates' HPA axis it became appa- ticoid aldosterone, whereas P450 l lj3-hydroxylase
rent that the SHRP is still a valid concept. However, )3111054P( defines the glucocorticoid producing zona
in order to confront this question, we will examine fasciculata/reticularis. In many mammalian species
the development of several components of the HPA the development of the adrenal cortical layers and
axis. These include the adrenal, the pituitary, and the steroidogenic enzyme synthesis primarily occur
brain. during fetal life (Parker et al., 2001). However, cells
expressing P4501 l 3j clearly resolve into their cortical
layer by the third day after birth (Mitani et al., 1997).
SHRP, the adrenal, and corticosterone The development of adrenal cortical zones are
closely related to the development of the chro-
It si generally agreed that in response to most maffin cells of the adrenal medulla (Bornstein and
stressors the neonate fails to elicit adrenocortical Ehrhart-Bornstein, 2000). As shown by Bornstein and
response, or does so minimally (Walker et al., 2002). co-workers, a variety of regulatory factors produced
There are several features that characterize the and released by the adrenal medulla play an impor-
function of the pup's adrenal. The first and most tant role in modulating adrenocortical function. Iso-
obvious characteristic of the adrenal function during lated adrenocortical cells loose the normal capacity to
SHRP is that basal levels of CORT are consider- produce glucocorticoids, whereas culture of adreno-
ably lower than that observed immediately following cortical cells with chromaffin cells causes marked
parturition and that these low basal levels continue to upregulation of P450 enzymes and the steroido-
predominate between postnatal days 4-14. Further, genic regulatory protein (STAR), which mediates the
numerous investigators have reported that the transport of cholesterol to the inner mitochondrial
neonate can elicit a significant increase in plasma membrane where steroidogenesis occurs (Bornstein
CORT levels (Walker et al., 2002). However, invari- and Ehrhart-Bornstein, 2000). On the 18th day of
ably the magnitude of the response is small compared fetal life, cells containing tyrosine hydroxylase (TH),
to older pups that are outside the SHRP and of the initial and rate-limiting enzyme of catecholamine
course to the adult. Thus, whereas the reported synthesis, and a marker for adrenal medullary cells,
changes in CORT levels following stress in the adult are found intermingled with cortical cells expressing
3111054P in the area that is later defined as the ZF/ administration. However, in one study at postnatal
ZR. However, the adrenal medulla becomes a well- day ,21 the ratio of free versus total corticosterone
defined morphological region at the end of the first is much higher in the neonatal rat than in the adult
week of life (Pignatelli et al., 1999), at a midpoint (Henning, 1978). Further, the clearance of CORT
in the SHRP. Within this period and until PND 29, from the circulation is significantly slower than the
the TH enzymatic activity increases (Lau et al., 1987). pup (Van Oers et al., 1998). Therefore, as a con-
It is during this time that most of the adrenocortical sequence, CORT is available for a more prolonged
cellular proliferation activity is observed, but limited period. The biologically active CORT has a more
to the outer cortex: ZG and ZF. Studies that utilized prolonged period of time to exert its effects in the
a specific antibody that recognizes antigens found periphery and the brain.
specifically in these cortical cells of the rat adrenal
(IZAgl and Ag2) showed faint ZF immunostain-
ing on the first day of postnatal life. A progressive Adrenal sensitivity
increase in staining was observed until 18-20 days
postnatally. Taken together, these data suggest that Although there appear to be rate-limiting factors that
the limited adrenocortical activity in the infant rat act developmentally to limit the secretion of CORT
is greatly due to the maturity of the steroidogenic in the neonate, evidence indicates that the adrenal
enzymatic pathways of the adrenal during the SHRP is actively suppressed during the SHRP. It has been
(see Fig. 2). In addition, there is evidence that extensively documented that certain aspects of the
suggests that the autonomic nervous system through rodent maternal behavior play an important role in
the adrenal medulla is also an important contributor regulating the neonate HPA axis. In particular, two
to the regulation of adrenocortical development specific components of the dam's caregiving activ-
through paracrine activity (Pignatelli et al., 1999). ities seem to be critical; licking/stroking and feeding.
Numerous studies have demonstrated that feeding is
in part responsible for the downregulation of the
Corticosteroid-binding globulin pups' capacity to both secrete and clear CORT from
the circulation (Suchecki et al., 1993; Van Oers et al.,
There is an important caveat in making the 1999). Thus, removing the mother from the litter
assumption that the reduced level of CORT following for 24 h results in a significantly higher basal level
stress indicates a reduction in biological activity. and a further increase in the secretion of CORT
CORT exists in the circulation in two forms, bound following stress or administration of ACTH. The
and unbound. The large majority of CORT in the authors have postulated that one of the consequences
adult is bound to cortisol-binding protein (CBG) and of maternal deprivation is to increase the sensitivity
other plasma binding proteins. Only a small fraction of the adrenal to ACTH (Rosenfeld et al., 1992). This
exists in the free form, which is considered to be has been demonstrated in several ways. (1) Signi-
the biologically active form. Following stress, CBG is ficantly lower doses of ACTH are required to induce
somewhat decreased, making more of the circulating the adrenal to secrete CORT. (2) Although the levels
CORT available as free CORT (Fleshner et al., 1995; of ACTH are equivalent between deprived and
Tannenbaum et al., 1997). Another aspect of the nondeprived pups under certain experimental condi-
SHRP in rodents is the relative absence of CBG tions, the levels of CORT are greater in deprived
during the SHRP (Henning, 1978). Thus, although pups. (3) Studies indicate that following mild stress
the absolute values of CORT, which normally include (injection of isotonic saline) there is an increase in
both bound and unbound hormone, are very low in c-fos gene expression in the adrenal cortex of the
the absence of CBG the actual fraction of CORT deprived neonate, whereas the nondeprived pup
that is available in the free form for binding to exhibited almost no detectable levels of c-fos
corticosteroid receptors may actually be higher than mRNA (Okimoto et al., 2002). If maternally deprived
is observed in the adult. There are few data on free pups are provided with food during the period of
CORT in the neonate following stress or ACTH maternal deprivation, both basal and stress levels of
CORT no longer differ from mother-reared pups. age of the neonate, the type of stress imposed, and,
Although a clear mechanism has not been elucidated, once again, maternal factors (Walker et al., 1991;
it is possible that the gastrointestinal-mediated Walker and Dallman, 1993). The early findings con-
activity of the autonomic nervous system may cerning the stress response of the pituitary suggested
regulate this phenomenon. that there was a deficiency in the neonates' capacity
At this time the physiological consequences of to synthesize ACTH. Thus as a result, the pup should
these changes in the exposure to high levels of CORT exhibit a reduction in the magnitude of the ACTH
in the deprived pup are not known. Studies have stress response. However, sufficient data indicate
shown that exposure to high levels of glucocorticoids that the pituitary of the neonate does have the capa-
during development have profound long-term effects city to synthesize and release ACTH that resembles
on the developing brain (Bohn, 1984). It should be the adult response. What seems to discriminate the
noted, however, that many of these studies used neonate from the adult is that for the pup the
pharmacological doses of adrenal steroids and, in response of the pituitary is much more stimulus-
many cases, used hormones that were atypical for the dependent (Walker et al., 1991). Further, the ability
rat (cortisol, dexamethasone). With the availability of to terminate the stress response is also not fully
the maternal deprivation model, only recently has developed and does not mature until quite late in
it been possible to achieve elevated levels of CORT development (Vazquez and Akil, 1993a). Perhaps the
that are generated endogenously by the pup. earliest demonstration that the neonate can indeed
mount an ACTH response to at least some types
of challenges was a study that challenged neonates
Corticosteroid clearance
with an injection of endotoxin throughout the period
from birth to weaning (Witek-Janusek, 1998). At all
Evidence of reduced clearance of CORT was obtained
ages the neonate exhibited a significant elevation of
in a study that examined the ontogeny of negative
ACTH that, beginning day ,5 was equivalent to the
feedback regulation (Van Oers et al., 1998). The
adult. Of interest is that although there was a robust
technique employed to study negative feedback in
ACTH response, the CORT response was reduced
the neonate was to adrenalectomize (ADX) the pup
markedly from day 5 and did not begin to approach
and to measure ACTH following ADX. Pups were
adult values until about day .51 The difficulty with
tested with and without CORT replacement. When
this study is that very large doses approaching the
deprived pups were implanted with the identical dose
lethal sensitivity of young rats to bacterial endotoxin
of CORT, their CORT levels were invariably higher
(0. 5-30 mg/kg) were used. It has been reported more
than those observed in nondeprived pups. This was
recently that administration of IL-13 elicited an
interpreted as indicating that clearance was reduced
ACTH response in pups as early as day 6 postnatal
as a consequence of reduced blood flow resulting
(Levine et al., 1994). The peak of the response
from 24h of fasting. Maternal deprivation there-
followed a similar time course to that of the adult,
fore alters the pattern of exposure to CORT as a
although the magnitude of the response was signi-
function of elevated CORT levels following depriva-
ficantly lower earlier in development. The reduced
tion that persist in the circulation and presumably in
response in day 6 neonates cannot, however, be
the brain of the developing pup due to reduced rates
interpreted as a reduction in the neonate's capacity
of clearance.
to produce ACTH. Three hours following ADX,
a robust increase in ACTH occurs as early as day ,5
SHRP and ACTH presumably due to the absence of a CORT nega-
tive feedback signal (van Oers et al., 1998). This
The concept of an absolute SHRP regarding the res- magnitude of the ACTH response is as great as that
ponse of the pituitary following stress in the neonate seen in older neonates at day ,81 which are well out
is much more problematic. Whether the pituitary can of the SHRP.
show an increase in ACTH in response to stress is It has been reported that the neonate does show a
dependent on numerous factors. Among these are the significant increase in ACTH in response to a variety
of different stimuli in an "adult-like manner." It is neuronally and produce the neuroendocrine cascade
noteworthy for each stimulus examined that appears required to activate the pituitary.
to be an idiosyncratic time course that is dependent A third factor appears to contribute to the reduced
on the age and the type of stimulus (Walker et al., capacity of the mother-reared pup to respond
1991). Regardless, it is apparent that the capacity to milder stress-inducing procedures. The role of
for a pituitary response is present early in develop- mothers caregiving activities on the developing adre-
ment. Under some circumstances the pup can show nal was discussed earlier. Evidence shows that mater-
a greater ACTH response early in development nal factors can also actively inhibit the release of
than later. Following treatment with kainic acid the ACTH (Suchecki et al., 1993; Van Oers et al., 1998;
ACTH response of day 21 pups exceeded that of day van Oers et al., 1998). Pups deprived of maternal
6 and day 81 neonates (Kent et al., 1996). The largest care for 24 h sowed an increase in ACTH following
ACTH response to N-methyl-D-aspartate (NMDA) an injection of saline as early as day .6 The effects
was at day .6 However, mother-reared pups failed to of maternal deprivation were even more apparent at
respond to milder perturbations. Brief periods of days 9 and .21 Although in subsequent experiments
maternal separation, exposure to novelty, injections the response at day 6 was not reliable, significant
of isotonic saline, and restraint for 30 min, all failed increases in ACTH were replicated in 9- and 12-day
to elicit an ACTH response in normally reared pups old neonates. These increases are also observed
until they escaped from the SHRP (Suchecki et al., following 30min of restraint. In contrast, nondepri-
1993). ved pups failed to show an acute release of ACTH
following stress. Whereas feeding was required in
order to reduce the sensitivity of the adrenal, ano-
Maternal behavior genital stroking can reverse the increased ACTH
secretion following deprivation (Suchecki et al.,
Why do neonates discriminate between different 1993). Thus, different components of the mother's
classes of stimuli, whereas older pups that have behavior appear to be involved in regulating different
escaped from the SHRP, and adults appear to res- components of the endocrine stress response. In pups
pond in a similar manner regardless of the stress- that were stroked and fed, both ACTH and CORT
inducing stimulus? Several hypotheses could account are suppressed (see Fig. .)1 In pups that received only
for this phenomenon. First it could simply be a stroking, ACTH was downregulated but CORT
matter of stimulus intensity. Thus, the neonate may was still elevated. These data would suggest that the
be less responsive to stimuli of lower intensities and dam's behavior was actively inhibiting the neuro-
may therefore require a more intense stressor to endocrine cascade that ultimately results in the
activate the neuroendocrine cascade that eventually peripheral endocrine responses to stress. Thus, the
leads to the release of ACTH. Second, it has been capacity to respond is present early in development
well documented that different stimuli activate but is only observable if the maternal inhibitory
distinct neural pathways that lead to the release of factors are not present. It is important to note,
CRF and thus ACTH. It is conceivable that the however, that although the pup can be induced
neural pathways that regulate the response to differ- to show an endocrine response to stress during the
ent classes of stimuli mature differently (Sawchenko SHRP, maternal inhibition is not the only rate-
et al., 2000), and thus if a particular stimulus activ- limiting factor. If one examines the body of data on
ates a pathway, which matures early in development the ACTH responses in pups, what emerges is that
then it is likely that a pituitary response will be even when the infant responds to mild stress during
manifest. Stimuli that threaten survival, such as the SHRP, the magnitude of the response is always
severe infection (endotoxin exposure) or hypogly- considerably lower in the SHRP than that of the
cemia, may fit this category. However, if the regulat- older pups (day )81 and adults (Dent et al., 2000a).
ing pathways are developing more slowly, such as It has been concluded that during the SHRP
stimuli that require some level of associative proces- the neural pathways regulating the ACTH response
sing, these stimuli may not be able to be processed to these milder stimuli are not as yet mature or that
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~=L~ 100- T ::!:::.: ::!i!~:l: :.: .~ 08
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~ ~ E O240 0- PE)1N :-:..................(cid:12)9 ...,.,. .........P.E.D-..............---..--.. , .. ............. ....,............... .- ............ ............-.-.:........ : .. .......... .......... . . .--....-......:.....-..--..- .. l .:...-...3.... : .. ------........--....-.. .. .. (cid:12)9 dekortS ! deF &Stroked 100 - NDEP i :iii:i,i:':iii:i:!,i PED: 'i :i,,:::..i.::i".. i........:.:...., .....,i:.........:..:... .! .i "::': ": Stroked t deFt &Stroked 0042 0 NI)EP ,~;:.::(cid:12)9 ,(cid:12)9 (cid:12)9 ....,,,.,,,,,, -,P,...,..,,,..,,ED:,,,,,.,.,. ..... .,,.....,,,,,,,,. ......,,., .. .,,(cid:12)9 ,,.,,,,,.,,,..,,,,. ,., .:,,..,:,,,,.,.,,.,.,:,.:,,.... ...! ,,,...,, :,,,:..,,,,,,,,,..,,.,,..,..:.,.,,,.,,,..,,: dekortS deF dekortS&
Fig. .1 Differential effect of feeding and anogenital stroking on HPA response in infancy. Plasma ACTH and CORT levels in 12-day
old pups are depicted on panel A, both under basal condition (NT) and 30min after a saline injection (STRESS). Basal CRF,
stress-induced (30min after saline injection) c-fos, and basal GR mRNA expression in the PVN of 12-day old pups are shown in
panel B. Litters were deprived for 24 h on pnd ,11 during which time they were left undisturbed (UND), stroked, or stroked and fed
episodically (n= 10-12/group). NDEP animals served as controls. * Significant from NDEP counterparts, p < 0.05. Adapted from
van Oers et al. (1999).