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REVIEW ARTICLE
The use of various animal models in the study of
stress and stress-related phenomena
w.
Sutanto & E. R. de Kloet
Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, University of Leiden,
PO Box 9503, 2300 RA Leiden, The Netherlands
Keywords
Stress; stressorsj animal models (laboratoryrat); genetic strain
Stress, defined as a disturbance in
homeostasis, was formulated by Hans Selye in
his 'general adaptation syndrome' concept
which described a biological stress syndrome
produced by diverse noxious agents.
According to this thesis, diseases of
adaptation were due to the development of
pathogenic situations in which many factors
participated. Stress affects the central
nervous system (eNS) leading indirectly to
the modulation of the activity of steroid,
catecholamine, peptide and opioid systems. It
also affects other body systems: behaviour,
the immune system, cardiovascular
responses and the gastrointestinal tract. In
response to stress, a cascade of
neurohumoral events chiefly at the level
of
the hypothalamic-pituitary-adrenocortical
IHPA) axis, is triggered, the result of which
is the termination of the stress reaction
leading to normalization (i.e. homeostasis).
Stress-induced events are complex
phenomena - a galaxy of factors are intricately
woven. Laboratory animals have been
indispensable in their roles as models in
the study of stress, and consequently in
shedding lights on our understanding of
what stress is about. This review will
summarize the most recent findings on the
use of laboratory animals as animal models
of stress and stress-related conditions, in
terms of (1) The use of various types of
animals, rats land mice) are 'favourite'
laboratory animals and genetically-selected
lines
I
strains have been developed for such
purposes. These include spontaneously
hypertensive rats and the corresponding
Correspondence
to:
Dr Win SuWnto
Accepted 14 February 1994
control Wistar Kyoto rats (SHR and WKY
respectively), apomorphine-susceptible and
apomorphine-unsusceptible rats (APO-SUSand
APO-UNSUS), Roman Low and High
Avoidance rats (RLAand RHA),
immunologically-altered Lewis ILEW
IN)
and
the corresponding controls Fischer IF344/Nl
and Wistar rats. (2) The use of different
types of acute and chronic stressors which
include forced swim-test, inescapable tail-
shock, immobilization, cold and ether stress.
In each of these cases, when appropriate, the
determination of endocrine and non-endocrine
parameters, and the purpose and implication
of these studies will be described. The
hypothalamic-pituitary-adrenal (HPA) axis
is the pivot for the animal's ability to
adaptation and coping with stressj its
activity is under stringent control of the
corticosteroid receptor systems in the eNS.
Note that the actions of corticosteroids
(and steroids in general) are mediated by
their specific receptors (see next section).
For this reason, when appropriate, the
findings from these studies will also be
discussed in terms of the plasticity of these
receptors (measured using an
in vitro
binding assay which allows for the
estimation of the receptor binding capacity
i.e. receptor density, and affinity) and the
consequences of such changes lin the receptor
system) in the animal's ability to
adaptation and coping with stress.
1. The HPA axis and central
corticosteroid receptors
The concept of stress has evolved, in the
past 40 years, from stimulus-induced organ
Laboratory Animals (1994) 28, 293-306
294
responses to psychosocial influences on
behaviour in which the experience of stress
and the handling of stressful information
were emphasized. The activity of the HPA
axis can be stimulated by psychological
factors such as uncertainty, conflict, lack
of control and information, or suppressed
by factors such as consummatory behaviour
and sense of control (de Kloet
et
01. 1991).
The activation and suppression of the HPA
axis is modulated by corticosteroids whose
action within the CNS are believed to be
mediated by two distinct corticosteroid
receptor systems: the mineralocorticoid
(MR) and
glucocorticoid (GR) receptors
(McEwen
et
01.
1986, Funder 1991, de
Kloet
&
Sutanto 1989). Radioligand binding
studies, immunocytochemistry and
cRNA/mRNA hybridization techniques
have made it possible to determine the
physico-chemical properties, topography
and gene expression of MR and GR in the
central nervous system (CNS) (Ahima
et a1.
1991, Herman
et
01.
1989, van Eekelen
et
a1.
1987). MR are localized in septo-
hippocampal region, anterior hypothalamus
and circum ventricular organs while GR are
more widely distributed throughout the
brain (Sutanto
et
01.
1988, van Eekelen
et
a1.
1987). MR are also localized in the
kidney (Sasano
et
01.
1992); in this tissue
they are ALDO-selective due mainly to the
specificity-conferring mechanism provided
by the enzyme 11~-hydroxysteroid
dehydrogenase (ll~-OHSD) [Edwards
et
01.
1988, Sakai
et a1.
1992). Moreover, in the
CNS, MR and GR mediate the different
action of corticosteroids. Thus, interaction
of corticosterone and/or cortisol (depending
upon the species) via MR in the hippocampus
is responsible for the tonic influences of
the steroid (de Kloet
et a1.
1991); the
interaction of mineralocorticoids (i.e.
aldosterone and deoxycorticosterone) via
MR in the anterior hypothalamus and
circumventricular organs controls sodium
homeostasis (de Kloet
et a1.
1989, McEwen
et a1.
1986, Yagil
et a1.
1986, Gomez-
Sanchez
et a1.
1990); and the interaction of
glucocorticoids via GR regulates stress-
activated neural metabolism and circuitry
i.e. it terminates the stress response and
Sutanto
&
de Kloet
controls the subsequent adaptive behaviour
of the animal (Akana
et a1.
1988, Dallman
et a1.
1987, Jones
&
Gillham 1988, Ratka
et a1. 1989).
Neuroendocrine studies have shown that
MR is important for the sensitivity of the
stress response system, while GR
suppresses stress-induced neuroendocrine
activation (Ratka
et a1.
1989). The
involvement of the hippocampus in
neuroendocrine feedback system and the
subsequent behavioural adaptation is also
well established (McEwen
et a1. 1986,
Meaney
et
01.
1992, Oitzl
&
de Kloet
1992). In a series of electrophysiological
studies, it has been shown that in the
hippocampus, MR-mediated effects of
corticosterone raise excitability of neuronal
cells which is suppressed by the steroid's
action via GR lJoels
&
de Kloet 1992a, b).
A balance between MR and GR-mediated
effects is of paramount importance for the
homeostatic control of the animal's stress
responsiveness and adaptation. If the
amount of MR relative to GR shifts, the
control of corticosterone/cortisol on
neuronal excitability, neuroendocrine
reactivity and behavioural adaptation may
change (de Kloet 1991).
2. Individual variability in response
to stimuli
There exist sex- and age-dependent
variations among individuals in response to
various stressors and other exogenous
stimuli as determined using a wide range
of physiological and biochemical endpoints.
The state and condition of the individuals
(i.e. individual variations) also playa major
part in this respect (e.g. Walker
et a1.
1992).
The effect of housing condition (isolated
vs.
grouped) of the animal on
adrenocortical secretion, for example, has
been known for a long time (Barrett
&
Stockham 1963). In animals housed in
single cages and undisturbed for 18 h, the
plasma corticosterone level is within the
normal range for basal value, and this
value doubles in rats which have been
housed in a large group. Further, elevation
Animal models in the study of stress
of plasma corticosterone following an
exposure to a novel environment is
significantly lower in singly-housed rats
than in group-housed rats. The former also
show less individual variation. The
locomotor activity, defaecation score and
corticosterone during an open-field
exposure are different between individually
and group-housed rats (Gentsch et
al.
1981).
Age is an important factor in determining
individual responsiveness. Senescence (or
ageing) is characterized by a general decline
in organ functions associated with a
decreased ability to maintain homeostasis,
while at ontogeny, during the first 2 weeks
of the rat's life, the neonate responds
poorly to a stressor (this period is the so-
called stress hyporesponsive period). Aged
rats, compared to the young controls,
exhibit less efficient HPA axis activity in
response to a stressor, as reflected also in
the animal's behaviour. For example, the
behavioural arousal induced by novelty
stress is delayed in the onset in aged rats,
or reduced in magnitude. In aged animals
and humans, stress-related cardiac
dysrhythmias and hypertension also occur,
which may involve autonomic dysfunction
[Buwalda et al. 1992). For detailed accounts
of the effect of age on stress
responsiveness} and stress-related
behavioural and neurochemical changes,
the reader is referred to the following
references: Benedetti et al. 1991, de Kloet
et al. 1988, Issa et al. 1990, Landfield 1987,
Landfield et al. 1981, Meaney et al. 1992,
Reul et al. 1988, Rosenfeld et al. 1988,
Sapolsky et al. 1983, Sato et al. 1991, van
Eekelen et al. 1992.
3. Genetically-selected rat lines/strains
It was proposed in the late 1960s that the
need to understand possible physiological
mechanisms underlying or accompanying
individual differences in behaviour among
humans and animals was a good reason for
the selection of various strains of rodents
(Treiman & Levins 1969). The use of
genetically-selected rat lines (inbred
selection) and strains (outbred selection)
295
has been a useful approach in this respect
since they serve as animal models, for
specific [patho- )physiological conditions,
which exhibit different physiological and
behavioural patterns, with the consequence
of differential responses to a stress
stimulus. Numerous genetically-selected
animal models have been developed to aid
in the study of endocrine and non-
endocrine parameters. These models have
been used for the study of the individuals'
differences in, for example, responses to
stress and other stimuli, vulnerability to
pharmacological agents, etc. The selection
procedure for rat lines/ strains started
around 30 years ago [e.g. Bignami 1965);
such selection has been based upon
physiological, behavioural and
pharmacological parameters and that the
selection traits have been maintained over
generations. The following models are
described in a greater detail in this review:
psychogenetically-selected rat line i.e. RHA
and RLA (Walker et
al.
1989, 1992)
pharmacogenetically-selected rat line i.e.
APOSUS and APO-UNSUS rats (Cools et
al.
1990), genetically selected strains SHR
and WKY rats (Bruhn
&
Jackson 1992,
Hendley et al. 1991, Hashimoto et al.
1989), and the immunologically-altered
LEW/N with autoimmune disease
[Sternberg
et al.
1989a, b, 1992,
Smith
et
al.
1992, Griffin
&
Whitacre 1991) and the
corresponding controls Wistar and Fischer
(F344/N) rats.
3.1 Psychogenetically-selected rat lines:
Roman High A voidance (RHA) and
Roman Low A voidance (RLA) rats
RHA and RLA rats are Wistar-derived rats
which originated from the early 1960s
(Bignami 1965). The selection is based
upon specific parameters of emotionality as
described in a review by Walker et
al.
(1992). Briefly, as part of a physiological
stress response, changes in the arousal
level and the behavioural state of the
animal occur. Changes in coping with
stress behaviour are generally classified
into different categories depending upon
whether a fight/flight or a freezing
response is the overall result. RLA rats
296
exhibit freezing behaviour (and they are,
therefore, poor avoiders) after being
subjected to foot shock stress; RHA rats
tend to flee, thus making them more active
avoiders. An analogy in the human is
illustrated in the differences in coping
styles following a phrase association task
between low-anxious, high-anxious and
repressive personalities (Weinberger
et al.
1979). In the rat, another example of
behaviour-based rat line selection is the
pharmacogenetically selected APO-SUS and
APO-UNSUS rats (see the following
subsection
3.2). The following rat
lines/ strains have also been selected for
various parameters of emotionality: The
Maudsley Reactive and Nonreactive rats
(Broadhurst
19751;
Syracuse
High
and Low-
Avoidance rats (Brush et al. 1988); the
Swiss sublines RLA/Verh and RHA/Verh
rats (Driscoll 1986, Driscoll
et al. 1990);
the Canadian sublines RLA/Lu and
RHA/Lu rats (Satinder 1981).
Apart from the aforementioned
behavioural differences, RHA/RLA rats also
show various non-endocrine and endocrine
differences
(0'
Angio
et al.
1988, Glavin
et
al.
1991, Sandi
et al.
1991, Walker
et al.
1989, 1992), some of which will be
described below. In the assessment of
activity of the HPA axis, stressful
environmental stimuli result in increased
hypothalamic serotonin turnover but
decreased dopamine metabolism in the
prefrontal cortex of RLArats. Stress-
induced increases in heart rate are greater
in RLA than in RHA rats
(0'
Angio
et al.
1988). RLA (compared to RHA) rats have
higher basal corticosterone levels at the
nadir and peak of the circadian rhythm;
they secrete a greater amount of
corticosterone after a mild stress [open
field), but not after an ether stress, and in
response to exogenous CRH challenge have
a greater pituitary ACTH output. In the
study of stress-induced ulcers in several rat
strains/lines, it has been shown that RHA
rats develop more starvation-induced ulcers
than RLA rats. Note that Maudsley reactive
rats (which resemble RHA in some
physiological and behavioural
characteristics) are more susceptible to
Sutanto
&
de Kloet
restraint-induced ulcers than Maudsley
non-reactive rats (see Glavin
et al. 1991,
for review).
The significance of the following findings
in the hyperemotional RLA rats is not yet
clear and certainly requires further
investigation: lower basal ACTH (but
higher corticosterone) levels, increased
pituitary sensitivity to CRH, lower
emotional response to a novel
environment, and the fact that they have
lower GR densities in the hippocampus and
anterior pituitary gland [as well as the
lower MR densities in the hippocampus, as
determined using
in vitro
assays; note the
parallelism between the receptor densities
to those found in the APO-SUS/APO-
UNSUS rats described in
subsection
3.2).
It
is possible that the high corticosterone
output in the presence of relatively low
circulating ACTH levels in RLA rats is due
to adrenal hypersensitivity in these rats,
and that the elevated corticosterone levels
exert a stronger inhibitory influence on
CRH/ ACTH release (despite the lower GR
and/or MR densities). Nevertheless, these
studies have clearly shown that the basal
and stimulated HPA activity is different in
these two rat lines, and that some of these
differences may be explained by (a)
pituitary sensitivity to CRH, (bl alterations
in corticosteroid receptor populations
[especially those in the hippocampus) and
the accompanying glucocorticoid feedback
system to the brain and/or pituitary, and
lc) corticosterone clearance rate and
binding to its protein carrier, corticosteroid
binding globulin (CBG, transcortin), and
free circulating corticosterone levels.
3.2 Pharmacogenetically-selected rat lines:
apomorphine-susceptible (APO-SUS) and
apomorphine-un susceptible
(APO-UNSUS) rats
The pharmacogenetically-selected rats
(APO-SUSand APO-UNSUSI are selected
based on the differential response to the
dopamine agonist apomorphine (Cools
et
al.
1990). It has been previously known
that rats belonging to a single outbred
colony of Wistar rats can show highly
individually-specific behavioural responses
Animal models in the study of stress
as exemplified in a defeat test where
certain rats flee and others freeze. The
fleeing response correlates with the amount
of gnawing elicited by the dopamine
agonist apomorphine. The breeding of the
subsequent generations resulted in
selection of APO-SUS and APO-UNSUS
rats which have subsequently been used to
examine the reactivity of the HPA axis in
relation to central catecholaminergic
systems. Preliminary data from our
laboratory have clearly indicated that APO-
SUS rats (which have a lower functional
dopaminergic activity and increased D
2
receptor affinity in the dorsal striatum)
show enhanced HPA response following a
stress situation as indicated by an
enhanced ACTH and free corticosterone
levels and an enhanced responsiveness of
the pituitary-adrenal axis to CRF
administration (Rots
et al.
unpublished).
The interline differences are also shown in
the rat's behavioural patterns. In general,
APO-SUS rats are marked by a high degree
of extrinsic organization of their behaviour,
whereas APO-UNSUS rats are marked by a
high degree of intrinsic organization (or
self-organization) behaviour. For example,
APO-SUS rats show much more novelty-
induced ambulatory behaviour than APO-
UNSUS, they are more bound to novel,
external stimuli, they have more difficulty
in switching to behavioural patterns
[including habituation) which are not
signalled by external stimuli
per se.
In the
open-field test, APO-SUS rats display an
increased locomotor activity and a fleeing
response in a defeat test compared to the
APO-UNSUS rats lCools
et ai.
1990, Oitzl
et ai.
unpublished).
The 2 rat lines also show interline
differences in their corticosteroid receptor
profile in the CNS. APO-SUS rats show a
significant increase in the hippocampal and
pituitary MR (but not GR) binding
capacities (but not the affinity) compared
to those in the APO-UNSUS rats. In the
hypothalamus, no difference in the binding
capacity of MR or GR is observed between
the 2 rat strains (Sutanto
et ai.
1989). In
view of the fact that the limbic
(hippocampal) MR exert control on basal
297
activity of the HPA axis during the
circadian rhythm and seem to be involved
in the control of the animal's responsiveness
to change as mentioned earlier in this
chapter (de Kloet 1991, for review), the
interline differences in the density of MR
in the hippocampus are of interest since it
may explain the interline differences in
behaviour and the activity of the HPA-axis
[Cools
et ai. 1990).
3.3 Immunologically-altered rat strains:
Lewis (LEW IN) rats
The Lewis (LEW
IN)
rat is a prototype
strain for the study of a number of
experimental autoimmune diseases
including experimental autoimmune
encephalomyelitis (EAE),uveitis (EAU),
orchitis (EAO) and adjuvant-induced
arthritis (AA). These rats, which are
Wistar-derived inbred rats also develop
arthritis in response to group A
streptococcal cell wall peptidoglycan
polysaccharide (SCW) while the
histocompatible Fischer
[F344/N)
rats do
not develop arthritis in response to the
same SCW stimulus. LEW
IN
rats have a
blunted HPA axis reactivity (Sternberg
et
al. 1989a, b) as shown in markedly
impaired plasma ACTH and corticosterone
responses to SCW (and other SCW stimuli),
as well as deficient paraventricular nucleus
CRH mRNA levels and hypothalamic CRH
content in response to the antigen. The
defective LEW
IN
corticotropin and
corticosterone responses to inflammatory
and other stress mediators, and the
susceptibility of the LEW
IN
to experimental
arthritis are due in part to a hypothalamic
defect in the regulation (i.e. synthesis and
secretion, but not the gene) of CRH.
Interestingly, LEW
IN
rats are less prone to
water-restraint induced ulcers than
F344/N
rats (see Glavin
et ai.
1991 for review).
These studies also show that LEW
IN
rats, compared to
F344/N,
have smaller
adrenal glands and larger thymus. However,
results from our laboratory using Wistar
rats clearly show that the adrenal weight is
similar in the 2 strains while the thymic
weight of LEW
IN
is less than that of the
Wistar. In another report (Griffin
&.
Whitacre
298
1991) significant differences in the
circadian rhythm of plasma corticosterone
and immunoreactivity were found across
sex and strain (LEW
IN
vs.
F344/N).
Male
LEW
IN
rats have significantly lower 24-h
corticosterone levels (but higher
mononuclear cell counts, particularly the
T-helper, CD4) than female LEW
IN
or
male
F344/N
rats. It is plausible that these
factors (i.e. low basal circulating
corticosterone and comparatively higher
numbers of CD4-bearing lymphocytes), may
playa causative role in the known
susceptibility of this strain to many
experimental models of autoimmune
disease.
It has been proposed that rat strains may
be differentially susceptible to autoimmune
disease induction depending upon the
magnitude of their corticosterone response,
either as circadian change or in response to
external stimuli (Sternberg
et al.
1989a, h,
Mason 1991). The susceptibility of LEWIN
(to arthritis) is due to its inability to
mount a steroid response comparable to
that in the disease-resistant strain. In
response to stress or trauma, glucocorticoid
levels increase in order to prevent the
initiation of autoimmune responses to
sequestered self-antigens produced as a
result of the injury. Corticosteroids,
therefore, seem to playa major influence
in the genesis of arthritis in LEW
IN
rats;
thus dexamethasone decreases the severity
of SCW-induced arthritis in these rats
while treatment of
F344/N
rats with the
potent glucocorticoid receptor antagonist
(RU 486) results in the development of
severe inflammatory disease (including
arthritis) in response to SCW (Sternberg
et
al.
1989a). In view of the fact that the
action of corticosteroids is mediated by
their specific receptors (see Section 1), we
have examined the corticosteroid receptor
population in various regions of the CNS
which are believed to be important in the
regulation of the stress (and stress-
immune) response (Sutanto
et al. 1992).
Thus in comparison with the
inflammation-resistant Wistar rats, LEW
IN
rats show a much greater (over 2-fold) MR
binding capacity in the hippocampus
Sutanto
&
de Kloet
without any change in the binding affinity,
while the GR capacity or affinity do not
differ. The hypothalamic MR capacity is
higher in LEW
IN
rats while the pituitary
GR capacity is lower in the LEW
IN
than
that in the Wistar rats.
3.4 Hypertensive rats: spontaneously
hypertensive and Wistar Kyoto rats
To study the mechanisms involved in the
regulation of cardiovascular system and
hypertension, various animal models for
hypertension have been developed. In the
early 1960s, Dahl and co-workers
selectively bred rats for susceptibility or
resistance to the hypertensive effects of
high salt intake freviewed in Rapp
&
Dene
1985).
Another type of genetically-selected
hypertensive rats are the spontaneously
hypertensive rats (SHR). When SHR are
used as a model of hypertension, the
normotensive Wistar Kyoto (WKY)rats are
used as the corresponding control.
Recently, 2 new strains of WKY rats have
been developed as a result of a cross
between WKY and SHR (Hendley
et al.
1991); one strain (WK-HT) are hypertensive
but not hyperactive while the other (WK-
HA) are hyperactive but normotensive. In
other words, hypertension and
hyperactivity in these rats are expressed
separately and these rats are used as
additional controls for SHR in studying
hypertension and hyperactivity.
In the following account, SHR (which
express hoth traits) and WKY (which
express neither) have been used. SHR have
a morphological abnormality in the HPA
axis related to the development of
hypertension, as indicated by the findings
that CRH concentrations in the median
eminence, cerebral cortex and posterior
pituitary are lower in SHR than in WKY,
that SHR show abnormal ACTH responses
to CRH or AVP injection, haemorrhage and
ether stress, and that plasma corticosterone
is higher in SHR (Hashimoto
et al.
1989).
Note that following the aforementioned
injection or stress, SHR show a greater
corticosterone response. This, together
with the elevated baseline corticosterone
level indicates adrenal hyperfunction which
Animal models in the study of stress
in turn, may be related to the development
of hypertension in this strain [Hashimoto
et
01.
1989). WKY rats are more susceptible
to develop water-restraint induced ulcer
than SHR (Glavin
et
01.
1991). This is
rather surprising when one considers that
WKY is normotensive and not hyperactive
(compared to SHR). However, WKY rats are
behaviourally depressed in the open field
behaviour test; they readily acquire a
learned helplessness response and exhibit
high floating scores in the Porsolt forced-
swim test. These behavioural patterns
indicate the presence of depression, and
certainly the link between depression and
ulcerogenesis cannot be ruled out (Pare
1989) since it is well known that patients
with depressive symptoms are more
susceptible to peptic ulcer disease
(Hernandez
et
01. 1988).
The importance of central corticosteroid
action (both mineralocorticoids and
glucocorticoids) in blood pressure
regulation and salt appetite is a well
known phenomenon (de Kloet
et
01. 1988,
McEwen
et
01.
1986, Griinfeld 1990,
Mantero
et
01.
1990). These studies have
shown that the effects of mineralocorticoids
on this regulatory system are mediated via
the central MR which include those
aldosterone-sensitive MR located in the
anterior hypothalamus and circumventricular
organs (see also: de Kloet 1991, for review,
Janiak
et
01.
1990). It is interesting to note
that these MR-mediated effects are
distinctly different from the GR-mediated
effects although the precise site where
these effects are exerted is not yet known
[van den Berg
et
01.
1990). What is known,
however, is the fact that patients with
hyperaldosteronism or with
hypercortisolism (e.g. Cushing's syndrome)
have higher blood pressure than the normal
subject. An analogous situation is observed
in SHR which have a higher basal blood
pressure than WKY rats.
Recently we have looked at the
differences in the corticosteroid receptor
systems in the brain and pituitary of SHR
and WKY (Sutanto
et
01.
1992). In the
hippocampus and hypothalamus of SHR,
the MR capacity (but not affinity) is greater
299
than that in WKY. A similar result was
also seen in the hippocampus of DOCA-salt
and renal-clip hypertensive rats in
comparison to their corresponding control
(Sutanto
&.
de Kloet, unpublished).
However, the hypothalamic [but not the
hippocampal) GR capacity is significantly
greater in WKY. In the pituitary, GR
capacity in SHR is greater than that in
WKY. The binding capacity of
corticosteroid-binding globulin [CBG,
trans cortin) for corticosterone is
significantly higher in SHR than in WKY.
In view of the fact that the aldosterone-
selective MR-mediated responses are
responsible for the elevation of blood
pressure (while GR-mediated effects result
in reduction in blood pressure) (Gomez-
Sanchez
et
01.
1990), it is plausible to
postulate that one of the factors responsible
for the higher blood pressure observed in
the SHR rats is linked to the higher MR in
the hippocampus and hypothalamus.
Certainly it has been shown that the
functional integrity of central MR is
required for the full development of
DOCA-salt hypertension (Janiak
et
01.
1990).
In conclusion, the use of genetically-
selected rat strains/lines is valuable for the
study of stress and stress-related
phenomena; they serve as animal models
for numerous (patho-lphysiological and
psychological conditions, and their use
enables the problem of individual
variations to be minimized. These animal
models have been used for the
investigation of endocrine (and non-
endocrine) stress-related phenomena. In
this respect, alteration in the activity of
the HPA-axis is of particular importance
since such an activity is a reflection (or an
index) of the animal's responsiveness to a
stressful situation. Coupled to this is the
plasticity of the corticosteroid receptor
(MR/GR) system in these animals. The
findings described in this section have
clearly indicated that life events (e.g.
stressful situations, condition of the
environment, genetic influence) have
profound effects on the corticosteroid
receptor profiles in the CNS.
300
4. The use of various stressors in
experimental animals
This section describes the various stressors
used in experimental animals, and the
resultant changes in endocrine and non-
endocrine parameters. The animal's
response to stress (and the individual
variation it displays) depends not only
upon the state and conditions of the
animal as described in the sections above
but also upon the nature (or type) of the
stressor itself, as well as the various
central (including, in this respect, the
animal's circadian rhythm) and peripheral
components, all of which affect the
animal's neuroendocrine response (and the
stress-related behavioural patterns).
4.1 Acute stress
When animals are subjected to acute stress,
a wide range of physiological alterations
take place. These changes can occur rapidly
such as in the case of increased plasma
ACTH level 5 min (or 30-45 min for
corticosterone) following a one-min ether
stress (Jones
&.
Gillham 1988, for review).
In a study using mice, exposure to noise
resulted in an increase in thymulin serum
level, thymic weight and the number of
thymocytes (Folch
et al.
1991). Other
forms of acute stressors are briefly
described below.
Immobilization stress has been used to
examine the activity of male rats in the
forced swim-test (Armario
et al.
1991) in 3
behavioural categories: struggling, mild
swim and immobility. In this study,
immediately after the 1h immobilization
in wood-boards, the stress reduced
struggling while restraint in tubes or tail
shock reduced mobility (Armario
et al.
1991, Cancela
et al.
1991). Twenty-four
hours after immobilization, a reduction in
struggling and mild swim test but an
increase in immobility was observed.
Immobilization or restraint stress (as do
other forms of stress) has a profound
influence on the animal's immune system:
In the pig, immobilization stress causes a'
suppression of the natural killer cells
(Tokarski
et al.
1992) while in mice,
Sutanto
&
de Kloet
restraint (in this case, 20 h at room
temperature) resulted in the suppression of
concanavalin A-induced lymphocyte
proliferation (Zha
et al. 1992).
The forced swim-test on its own is also a
stressor; when mice were swum for 3 min
at room temperature, the sensitivity to a
pentobarbital challenge increased as
indicated by a 70% increase in the
'sleeping time' i.e. the loss of righting
reflex in response to the drug (Carmody
et
al. 1991).
Acute tail-shock in the rat causes
increased plasma cholesterol levels
(Brennan
et al.
1992); it also enhances the
secretory activity of goblet cells in the
nasal mucosa (Tachibana
et al.
1991). In
the guinea pig, in the attempt to develop
an animal model for experimental nasal
hypersensitivity and hyperreactivity, the
animal was subjected to intermittent cold
stress (SARTstress) for 5 consecutive days
(Namimatsu et
al.
1991). Nasal mucosal
hypersensitivity to histamine and nasal
hypersecretion to methacholine were
observed. These hyperreactions are
apparently linked to the increase in the
muscarinic acetycholine receptors. The
authors concluded that SART-stressed
guinea pigs can serve as animal models for
hypersensitivity in nasal mucosa, which
would be useful in the study of nasal
allergy.
Ether has always been regarded as an
anaesthetic agent, however, ether
anaesthesia is by itself a stressor which
causes dramatic alterations in the activity
of the HPA axis components (Jones
&.
Gillham 1988, for review). In the study by
van Herck and co-workers (van Herck
et al.
1991), ether anaesthesia produces a marked
endocrine response i.e. it causes
pronounced increases in plasma levels of
selected stress hormones such as
corticosterone, adrenalin and noradrenalin.
In the same study, orbital puncture was
found not to amplify this response. It
appears, therefore, that ether anaesthesia
'masks' any effects (e.g. discomfort, pain)
of orbital puncture. The combination of
anaesthesia and blood puncture has also
been used successfully in the assessment of
Animal models in the study of stress
blood metabolites in lactating rabbits
(Mottaz
et al.
1991). However, ether
anaesthesia may not be a suitable
anaesthetic for studying other endocrine
end-points. For example, rats which were
previously exposed to ether anaesthesia
have reduced concentration of
neuropeptides (oxytocin, oxytocin-
neurophysin and its metabolite) in the
posterior pituitary (Zierer 1991).
Recently, 2 independent groups (Koolhaas
et al.,
Tilders
et ai.
both unpublished) have
shown that a short, single experience of
stress can have long-term consequences for
the animal's stress response. In the
Koolhaas' study, individually-housed rats
were subjected to a social defeat, followed
by an exposure to noise test. It appears that
a single social defeat is sufficient to induce
a gradual change in behavioural
responsiveness to a mild stress of sudden
silence in the noise test. In the work of
van Dijken and co-workers, rats exposed to
a single and short session of inescapable
footshocks showed long-lasting (observed
for at least 28 days) alterations in
behavioural responses to environmental
stimuli, accompanied by alterations in the
HPA activity, including changes in the
corticosteroid receptor profile in the CNS
(see Sutanto
et al.
1992). These findings
clearly indicate that a single stress
experience has profound changes in stress
responsiveness and behaviour. What is
essential in this respect is the fact that an
experience of stress, following an exposure
to a single stressor, is an important factor
in the long-term ability of the animal to
efficiently cope with and handle stress.
4.2 Chronic stress
Chronic stress has been linked to major
physiological and psychological illnesses in
humans. Certainly, evidence in the past
years has indicated that chronic stress is an
important factor in the development of
hypertension, gastrointestinal disorders,
immune suppression, reproductive
dysfunction and mental depression. The
use of laboratory animals has been
instrumental in investigating the
consequence(s) of chronic stress. Most
301
chronic stress models are in the form of
repeated exposure on a daily basis to
stressors such as cold, restraint or
intermittent foot-shock, to name but a few.
One predominant feature of this type of
regimen is the finding that repeated stress
leads to adaptation or habituation, hence
repeated exposure to the same stressor
evokes less of a hormonal response to each
stress session. This, again, depends very
much upon the type of the stress used
(Jones
&
Gillham 1988, Pitman
et ai. 1988,
Natelson
et al.
1988). For example,
repeated restraint stress exposure resulted
in increased dopamine release which
returned to basal 1 h later [Imperato
et al.
1992). However, the mesolimbic
dopaminergic system 'adapts' to the
repeated stress stimuli - no more increase
was observed on the 4th day onward.
Natelson and co-workers (Pitman
et ai.
1988, Natelson
et ai.
1988) in their study
of the effect of stressor intensity on
adrenocortical stress response over time
have shown that individual differences in
reactivity to stressors (as well as the
stressor intensity itself) can influence the
pattern of the stress response over the
course of repeated administration of the
stressor. There seems to be 'intraspecific
communication of the intensity of stress',
i.e. the responses in control rats for the
more intense restraint stress did not
habituate completely in 7 days whereas the
responses in the rats for the milder
(restraint) stress habituated completely
within 3
days.
Chronic or repeated stress thus causes a
wide range of physiological and
neuroendocrine changes. For example,
chronic stress in the form of constant
illumination resulted in the disruption in
the circadian patterns of corticosterone,
progesterone and melatonin (Persengiev
et
al. 1991).
In the study of Kant and co-workers
(Kant
et ai.
1987), rats were given
footshock daily for 14 days. Seven days of
this treatment resulted in increased adrenal
weight and decreased thymic weight (these
are classic indices for a stressful paradigm).
However, rats maintained on this paradigm
302
for 14 days are able to maintain escape
behaviour, eat and drink, gain weight and
groom. When the effects of this stressor on
the levels of 3 stress-responsive hormones
(corticosterone, ACTH and prolactin) were
examined, it appeared that levels of plasma
corticosterone were elevated during the first
7 days in the stressful environment (but
returned to control by day 14), although the
levels of plasma ACTH and prolactin were
similar in stressed and control animals at
all time points measured. It appears,
therefore, that at least for this type of
stress, changes in glucocorticoids, but not
ACTH or prolactin, mediate [some of) the
physiological changes that occur as a result
of chronic stress.
Chronic stress (as well as acute stress) is
a potent inducer of stress ulcers. The term
'stress ulcer' encompasses upper
gastrointestinal haemorrhage and lesions as
a consequence of a variety of factors
including burns, intracranial trauma and
systemic infections in man (Glavin
et al.
1991, for review). In the experimental
animal models for stress ulcer, the most
commonly employed methods for
experimental ulcer induction in rats are
cold restraint, water restraint, shock stress
and (partial) food deprivation. The animal's
ulcerative response to a stressor depends
upon predisposing factors (age, sex,
strains/lines, early experiences), the nature
of the stress employed to induce the ulcer,
and the post-stress events (i.e. the events
occurring after termination of
stressj
this
process is modulated by psychological!
learning factors).
The (neuro)endocrinological basis of
stress ulcerogenesis remains unclearj the
existence of brain-gut axis (and that the
process of ulcerogenesis is a brain-driven
one) has been proposed. Parts of the limbic
system (amygdala and hippocampal
formation) may modulate (positively or
negatively) the degree to which stressful
experiences produce pathological changes
in the gastrointestinal system.
5. Concluding remarks
Stresses may lead to various (patho-)
Sutanto
&
de Kloet
physiological and biochemical changes.
This review has attempted to answer the
questions: How do animals respond to
stress? How do they cope and adapt? The
ability to adapt to stressful situations
depends on the housing, sex, species and age
of the animal, and its individual adaptability.
Individual variability renders it difficult
to pinpoint the mechanism(s) involved in
the animal's response to a stressor. In this
respect, the development and use of
genetically-selected animals have helped to
overcome this problem. The individual
differentiation (Section
31
appears to be
valid across lines and strains of rats (e.g.
RLA
vs. RHAj
SHR
vs. WKYj
APO-SUS
vs.
APO-UNSUS). This type of study therefore
lays a foundation for understanding fat least
in part) the physiological basis underlying
the differences between 2 fundamentally
different types of individuals (as shown in
individual trait characteristics both in
physiology and
behaviour) existing in the
normal population of animals. Moreover,
these animal models have been particularly
useful in deciphering and defining the
mechanis:ms involved in coping and
adaptation to stress. Data from animals
studies are not necessarily applicable to
human situations but nevertheless, studies
using animals having conditions which
mimic certain physiological and patho-
physiological situations, may help to
understand idiosyncratic characteristics
both in animals and in man.
A whole range of physiological, behavioural
and biochemical parameters have been used
for the assessment of the animal's response
to stress, as described in the last section of
this review. The findings from studies of
corticosteroid receptor plasticity in the
CNS clearly indicate that stress,
environment and strain have profound
effects on the corticosteroid receptor gene
expression in the brain and pituitary.
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