Physiology & Behavior, Vol. 40, pp. 775-779.PergamonJournals Ltd., 1987. Printedin the U.S.A. 0031-9384/87$3.00 + .

00

Effects of Chronic Stress

on Plasma Corticosterone,
ACTH and Prolactin '
G. J E A N K A N T , J O H N R. L E U ,
S A L L Y M. A N D E R S O N A N D E D W A R D H. M O U G E Y

D e p a r t m e n t o f Medical Neurosciences
Walter R e e d A r m y Institute o f Research, Washington, D C 20307-5100

R e c e i v e d 18 S e p t e m b e r 1986

KANT, G. J., J. R. LEU, S. M. ANDERSON AND E. H. MOUGEY. Effects of chronic stress on plasma corticosterone,
ACTH and prolactin. PHYSIOL BEHAV 40(6) 775-779, 1987.--Rats were placed in a stressful environment for 24 hr per
day and levels of plasma hormones were measured after varying numbers of days in the environment. Rats were habituated
to operant chambers placed in sound-attenuated enclosures. Food pellets were available by lever press on a FR1 schedule.
After 3 days of habituation, rats in the "stressed" group were trained to pull a ceiling chain to avoid or escape shock.
Following training, stress trials, consisting of a consecutive sequence of 5 sec each of a warning light, warning tone and
0.16, 0.32, 0.65, 1.3 and 2.6 mA of footshock, occurred approximately once per 5 min around-the-clock. For the first day,
the sequence was terminated when the ceiling chain was pulled. On subsequent days, 90% of all shock presentations could
be avoided or escaped by chain pull; the remaining 10% of trials were inescapable and the entire sequence was presented.
Control rats lived in identical chambers without presentation of shock. Rats were sacrificed after 1, 2, 3, 4, 7 or 14 days in
this environment and levels of plasma dorticosterone, ACTH and prolactin were determined. Levels of plasma corticoste-
rone were elevated during the first 7 days in the stressful environment, but returned to control values by day 14. Levels of
plasma ACTH and prolactin were similar in stressed and control rats at all time points measured. These data suggest that
stress-induced changes in giucocorticoids but not in ACTH or prolactin might mediate some of the physiological changes
that occur as the result of chronic stress.

Stress ACTH Prolactin Corticosterone

CHRONIC stress has been linked to major physiological and
psychological illness in humans. Stress has been suggested
to be important in the development of hypertension, gas-
trointestinai disorders, immune suppression, reproductive
dysfunction and mental depression [1, 2, 5, 8, 10, 12, 13, 30,
35, 36, 41]. Hormones appear to play a role in the develop-
ment of some of these disorders. Adrenal catecholamines
may be involved in the development of hypertension [29].
Cortisol regulation appears to be abnormal in some depress-
ive illness and cortisol appears to be a significant factor in
immune suppression [1, 9, 25]. Prolactin may also be in-
volved in immune regulation and in regulation of reproduc-
tive functions [4,14]. Accordingly, laboratory investigations
of the effects of chronic stress on levels of plasma hormones
have proved useful in determining the potential role of these
hormones in stress-induced illness.
Most animal studies of stress have been conducted in
acute models in which a single relatively short period of
exposure to a stressor has been utilized. These studies have
shown that acute stress rapidly activates central and periph-
eral neuronal pathways and causes the release of pituitary
and adrenal hormones [6, 7, 16-18, 23, 26, 32-34]. These
hormonal responses facilitate physiological and metabolic
changes, e.g., increased release of glucose and increased
heart rate, that are useful in meeting the immediate stress
challenge.
Most "chronic" stress models generally have involved
repeated exposures to stressors on a daily basis. Repeated
daily exposure to cold, restraint or intermittent footshock
are often used as animal models of chronic stress [19, 21, 22,
24, 38, 39]. The predominant reported hormonal response to
repeated stress is adaption or habituation such that repeated
exposure to the same stressor evokes less of a hormonal
response to each stress session [19, 21, 24, 38, 39]. In the
interval between daily stress sessions, hormonal levels ap-
pear to be similar to those seen in non-stressed controls.
Thus there is complete recovery from stress-induced
changes in hormonal levels between stress sessions.

'The views of the author(s) do not purport to reflect the position of the Department of the Army or the Department of Defense (para 4-3, AR
360-5). Research was conducted in compliance with the Animal Welfare Act, and other Federal status and regulations relating to animals and
experiments involving animals and adheres to principles stated in the Guidefor the Care and Use of Laboratory Animals, NIH publication
85-23. All procedures were reviewed and approved by the WRAIR Animal Use Review Committee.

775
776 KANT, LEU, A N D E R S O N AND MOUGEY

TABLE 1 significant perturbation of plasma corticosterone which per-

EFFECTS OF SUSTAINEDSTRESS ON LEVER PRESSINGFOR FOOD sists for the first week of the paradigm. Plasma levels of
ACTH and prolactin remained similar to controls at all time
Lever Presses points measured.
Stress METHOD
Duration Control Stressed Significance
Animals

0-day 476 _ 29 483 _+ 31 n.s. Male Sprague Dawley rats (300___50 g) were purchased
1-day 539 + 28 320 +__43 p<0.05 from Zivic-Miller and habituated to an animal housing room
2-day 464 _+ 38 265 _+ 38 p<0.05 for 2 weeks prior to each experiment. F o o d and water were
3-day 572 _+ 70 420 _ 45 n.s. freely available. Animals were individually housed in hang-
4-day 556 _+ 39 352 +- 43 p<0.05 ing wire cages. Lights were on from 0600 to 1800 daily.
7-day 511 _+ 13 370 _+ 23 p<0.05
14-day 501 ___29 465 _+ 40 n.s. Experimental Apparatus
Six or eight operant chambers housed in sound-
Values represent the mean _ SEM. 0-day stress represents bar attenauted enclosures and equipped with floorbars, lever,
presses for each group for the 24 hr prior to shock initiation for the house light, warning lights, sonalert, and ceiling chain were
stress group. Values were compared using Student's t-test (two- used in these experiments. All behavioral testing apparatus
tailed). Results were considered to be significant at p<0.05. N for was purchased from Coulbourn Instruments. The apparatus
each number of days for control and stress in (C,S): l-day (6,4);
2-day (11,10); 3-day (8,8); 4-day (16,15); 7-day (7,8); 14-day (11,12). was controlled and data collected by a DEC-PDPSA com-
0-day food intake represents the mean of 67 controls and 62 stressed puter programmed in SKED. Lever presses and chain pulls
animals. were recorded in 1 hr bins.

Stress in humans, however, may sometimes be more
constant, without extended periods of rest between stress
episodes. Long-term illness, grief over the death of a family
member, financial worries, fear of failure or service in a
battle zone might be considered to be sustained stressors. In
order to investigate the hormonal effects of such sustained
stress, we have recently described and characterized an
animal model that incorporates 24 hr per day stress, sleep
disruption and a continuous performance requirement [27].
In this stress model, rats are housed around-the-clock in
operant chambers; food pellets are available via lever press
on a FR1 schedule. After rats are habituated to the cham-
bers and have learned to lever press for food, some rats
(stressed) are trained to escape footshock by pulling a ceiling
chain. Following training, stressed rats are presented with a
stress trial approximately once per 5 min. A stress trial con-
sists of 5 sec each o f a warning light, followed by a tone,
followed by 5 levels of escalating shock (0.16, 0.32, 0.65, 1.3,
and 2.6 mA). A ceiling chain pull at any point during the
sequence terminates the presentation immediately. During
the first 24 hr of the paradigm, all shocks can be avoided or
escaped. After the first 24 hr, rats avoiding or escaping more
than 75% of trials are placed on a schedule with 10% of the
trials inescapable; pulling the chain on these trials has no
effect and the trial continues through all shock levels (a total
of 35 sec). We have previously shown that rats maintained
on this paradigm for 14 days are able to maintain escape
behavior, eat and drink, gain weight and groom. However,
food intake is depressed compared to non-shocked controls
during the first 7 days of the experiment, adrenal weight is
increased and thymus weight decreased in the stressed
animals [27]. Therefore, the paradigm is stressful, as judged
by these classic indices [3, 38, 39], yet it appears to be toler-
able for up to 2 weeks without significant debilitation.
In the present report, we have studied the effects of this
stressful environment on levels of three stress-responsive
hormones, ACTH, corticosterone and prolactin. Animals
were exposed for 1 to 14 days in the paradigm prior to
sacrifice and hormone measurement. The results point to a
Experimental Procedures
In each experiment, six or eight rats were placed in the
operant cages and given three days to habituate to the en-
vironment and learn to lever press for food. On the fourth
day, one half of the animals (3 or 4 depending on the experi-
ment) were trained to pull a ceiling chain to avoid scrambled
footshock delivered by the experimenter. Following training,
shock trial sequences were controlled by the PDP8A. Each
trial consisted of 5 sec of warning light (a triple cue light was
illuminated), 5 sec of a sonalert tone, and 5 sec each of
escalating footshock (0.16, 0.32, 0.65, 1.3, 2.6 mA). Trials
were presented at approximate 1 rain intervals until 35
avoidances or escapes were recorded. Then the frequency
was reduced to one trial per 5 rain (average intertrial inter-
val). During the first 24 hr, all trials were avoidable or escap-
able. On the second and following days of shock trials, rats
avoiding or escaping more than 75% of trials were placed on
a schedule where 10% of the trials were inescapable (chain
pull had no effect). Performance was reviewed daily and rats
failing to escape more than 75% of escapable trials were
placed back on a 100% escapable schedule.
Plasma Collection and Assay Procedures
Following 1, 2, 3, 4, 7, or 14 days of shock trials, animals
were sacrificed and trunk blood collected in hepadnized
beakers. Rats were sacrificed between 0930 and 1130 in each
experiment to minimize the effects of diurnal rhythms on
levels of plasma hormones [20,28]. Rats were sacrificed at
this time so that resting levels of corticosterone would be low
and stress-induced elevations would be easily seen. The
blood was centrifuged and Trasylol (aprotinin, a peptidase
inhibitor) was added to plasma samples for the ACTH assay.
All plasma was stored at -40°C until assayed by
radioimmunoassays. Separate assays for each hormone
were performed for each experiment. Two 1-da:' stress exper-
iments were performed; three 2-day stress experiments were
performed; two 3-day stress experiments were performed; four
4-day stress experiments were performed; two 7-day exper-
iments were performed and three 14-day experiments were
performed.
STRESS AND PLASMA HORMONES 777

12.O- TABLE 2

[i"'I
il.O- EFFECTS OF SUSTAINEDSTRESS ON PLASMAACTH
I0.0-
ACTH (pg/rnl)
E 9.0-
Stress
8.0- Duration Control Stressed Significance
l=m / X\I
7.0"
1-day 65.2 __- 13.3 46.8 __+ 7.3 n.s
Z 6.0- \% 2-day 69.8 _+ 9.5 76.8 _+ 11.8 n.s.
c~ 5.0- 3-day 57.3 _ 15.1 41.5 _ 9.2 n.s,
NN.%% 4-day 54.6 -4- 9.6 55.7 -+ 5.6 n.s,
4.0-
,.¢- 7-day 56.3 -+ 7.8 49.1 -+ 7.3 n.s,
3.0- 14-day 78.3 __- 10.3 91.6 - 18.2 n.s.
2.0"
i Values represent the mean -+ SEM. Values were compared using
I.O-
Student's t-test (two-tailed). Results were considered to be signifi-
cant at p<0.05. N for each number of days for control and stress in
0.0
; ~ ~ ~. (C,S): 1-day (6,6); 2-day (11,10); 3-day (8,8); 4-day (12,11); 7-day
DAY (7,8); 14-day (11,12).

FIG. 1. Effects of sustained stress of varying duration on levels of

plasma corticosterone. Solid lines and circles denote controls;
dashed lines and open circles represent stressed animals. Data from TABLE 3
different experiments performed over 6 months are combined. Val- EFFECTS OF SUSTAINEDSTRESS ON PLASMAPROLACTIN
ues represent the mean_+SEM. Values were compared using Stu-
dent's t-test (two-tailed). *Significantly different than matched con- Prolactin (ng/ml)
trol group. N for each number of days for control and stress in (C,S):
1 day (6,6); 2 day (11,10); 3 day (8,8); 4 day (16,14); 7 day (7,8); 14 Stress
day (11,12). Duration Control Stressed Significance

Materials for the prolactin assay were provided by the 1-day 5.9 -+ 1.2 7.2 -+ 0.6 n.s.
National Institute of Health through the National Hormone 2-day 10.0 -+ 2.2 9.0 _+ 0.9 n.s.
and Pituitary Program. Prolactin was radioiodinated as pre- 3-day 9.3 -+ 1.6 6.1 -+ 0.9 n.s.
viously described [26]. Within assay variation was <8% and 4-day 5.3 -+ 1.3 4.2 -+ 0.6 n.s.
between assay variation <12%. 7-day 5.8 -+ 1.1 6.0 _+ 0.4 n.s.
Corticosterone was measured by radioimmunoassay 14-day 4.2 -+ 0.7 6.0 _+ 2.0 n.s.
using an antibody produced in our laboratory against
corticosterone-21-hemisuccinate:BSA. Somogyi reagents Values represent the mean -+ SEM. Values were compared using
were used to separate free from bound ligand [31]. Student's t-test (two-tailed). Results were considered to be signifi-
Corticosterone[1,2-SH(N), specific activity 50 Ci/mmol, New cant at p<0.05. N for each number of days for control and stress in
England Nuclear] was the labelled ligand. Assay sensitivity (C,S): l-day (6,5); 2-day (8,8); 3-day (4,4); 4-day (4,3); 7-day (7,8);
was 0.6/~g~. The intraassay and interassay coefficients of M-day (7,8).
variance were 6% and 12% respectively.
ACTH was measured using a radioimmunoassay kit
(Immuno Nuclear Corp). Human ACTH was used as a RESULTS
standard. The assay was performed in 10x75 polystyrene
Lever pressing for food pellets was decreased in the
tubes using an overnight incubation at 4°C. Assay sensitivity
stress groups for the first 7 days of the shock paradigm but
was approximately 10 pg]ml. The intraassay coefficient of
returned to control levels by the 14th day (Table 1). Rats
variation was 2.5% at 370 pg/ml and the interassay coeffi-
escaped shock by pulling the ceiling chain during levels 3 to 4
cient of variation was <5%.
of shock, on the average (corresponding to 0.65 to 1.3 mA of
Statistics current). This behavior was maintained over the 14 day
stress period (data not shown).
Due to equipment limitations, only 6 or 8 animals could be Plasma corticosterone levels were elevated in stressed
tested in each experiment. Therefore more than one experi- animals as compared to controls following 1, 2, 3, 4, or 7
ment was performed for each number of days of stress. In days in the paradigm (Fig. 1). Following 14 days in the
each experiment, half of the animals were assigned to the paradigm, however, levels of corticosterone were similar in
stress condition and the other haft served as controls. Data control and stressed rats. The increased corticosterone
from all animals run for the same number of days in the levels on days 1 and 7, however, were not statistically signif-
paradigm were combined for each variable measured, al- icant due to the large variability within the stress groups.
though different experiments were separated in time by as Plasma ACTH (Table 2) and plasma prolactin (Table 3)
long as 6 months and plasma samples from each experiment levels were similar in control and stressed groups at all
were separately assayed for each experiment. Control and measured points.
stressed values for each stress duration were compared using
Student's t-test (two-tailed). Results were considered to be DISCUSSION
significant at p<0.05. Repeated exposure to the same stressor results in
 778
habituation of hormonal responses compared to the initial
evoked response. Habituation may involve decreased sen-
sitivity to the stressor (e.g., alteration in pain threshold),
decreased affective response to the same degree of stimula-
tion (e.g., decreased anxiety to a familiar stimulus) or an
altered biochemical response to a repeated stimulus (e.g.,
due to increased/decreased synthesis of a hormone or neuro-
transmitter). In the present experiment, the average shock
level at which rats pulled the ceiling chain to avoid/escape
shock remained at approximately the same point for the 14
day period. Thus, altered sensitivity to footshock is unlikely
to be the major factor involved in the observed habituation of
the corticosterone response. Thus either biochemical
changes in hormonal synthesis or release capacity or behav-
ioral adaptation to a repeated stimulus or a combination of
these factors may be involved in the observed habituation.
Since the stress threshold for responding is different for
different hormones, it is not surprising that different hor-
mones habituate at different rates [16, 19, 2t]. In the present
report, plasma ACTH and prolactin levels appeared to
habituate very rapidly, since levels following 24 hr of stress
were similar to levels seen in unstressed controls and since
both these hormones are known to increase markedly follow-
ing acute stress [20]. The effects of the stress paradigm on
food intake and corticosterone were longer-lasting and, in
fact, these two indices may be interrelated since food depri-
vation itself is a potent stressor [11,37].
The habituation of the prolactin response is consistent
with earlier reports which utilized models of repeated daily
exposures to cold, footshock, immobilization or forced run-
ning and which demonstrated a significant adaptation of
prolactin response, the speed of habituation depending upon
the intensity of the stressor and the duration of each daily
exposure [19, 21, 38, 39]. The constant exposure to stress-
ors, in the present experiment, caused a more rapid habitua-
tion than repeated daily exposure of relatively short dura-
tion. Following, for example, l0 days of repeated (15
min/day) immobilization, footshock or forced running,
prolactin responses were attenuated as compared to re-
sponses to the first exposure, but a significant response to
the tenth exposure was still evident [19,21]. Very long-term
(42 day) exposure to long durations (6 hr/day) of some
stressors has been reported to actually decrease prolactin
levels below control values [39]. It has also been shown that
repeated daily footshock sessions do not increase anterior
pituitary content of prolactin mRNA, although mRNA for
proopiomelanocortin peptides (POMC) is increased under
these conditions [15]. These different experiments all suggest
that while acute stress causes marked increases in plasma
prolactin levels, chronic stress does not result in increased
synthesis or release of plasma prolactin.
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