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6.. NAME OF PERFORMING ORGANIZATIO | 6b. OFFICE SYMBOL 7a. NAME OF MONITORING ORGANIZATION
Dept. of Medical Neurosciences (If appikable) Walter Reed Army Institute of Research
Walter Reed Army Inst. of Resch_
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Walter Reed Army Institute of Research Washington, DC 20307-5100
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11. TITLE (include Security Classfication)

ACTH, Prolactin, Corticosterone and Pituitary Cyclic AMP Responses to Repeated Stress
12. PERSONAL AUTHOR(S)
G.J. Kant, E.H. Mougey, J.L. Meyerhoff
13.. TYPE OF REPORT 13b. TIME COVERED 14. DATE OF REPORT (Year,Month,Day) 1I-PAGE COUNT
FROM ______TO -I
16. SUPPLEMENTARY NOTATION

17. COSATI CODES 18. SUBJECT TERMS (Continue on reverse if necessary and identify by block number)
FIELD j GROUP SUB-GROUP Stress, ACTH, Prolactin, Cyclic AMP Corticosterone, CRF.

I I
19. ABSTRACT (Continue on reverse if necessary ard identify by block number)

ACTH, prolactin, corticosterone and pituitary cyclic AMP responses to repeated stress
challenges with intervening rest periods. PHARMACOL BIOCHEM BEHAV.--The present experiment
was conducted to determine whether the plasma hormonal and pituitary cyclic AMP responses
observed following a single exposure to an acute stressor would diminish following
reexposures to the same stressor. Fifteen min stress exposures (forced running) were
separated by 45 min recovery periods. Separate groups of control and stressed animals were
sacrificed before and after each of four 15 min stress periods and after each recovery
period. The first exposure to 15 min of forced running raised plasma ACTH, corticosterone
and pituitary cyclic AMP levels approximately 6 fold and more than tripled levels of plasma
prolactin. Plasma ACTH and pituitary cyclic AMP responses to the second, third and fourth
stress exposures were very similar to the responses to the first stress exposure, and levels

20. DISTRIBUTION /AVAILABILITY OF ABSTRACT 121 ABSTRACT SECURITY CLASSIFICATION

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 ~ . . . (
8, . , '1 ~.pp i it I cr~&i t'urlPc-
s ) Puilcd In (tic t N5 A OHNI3)5
10 ') 9 13 ) IN)

ACTH, Prolactin, Corticosterone

and Pituitary Cyclic AMP Responses
to Repeated Stress'
2

G. JEAN K.-\NT. EDWARD H. MOUGEY AND JAMES L.. MEYERHOFF

l)tI)IIrtmcnt It dic0/ .\i u,.-
ur ,'te. Walter Recd Army In.iitutc ol Rcscarch
Wa.shin-, on, 1)(" 20307-5100

Received 15 June 1988

K.*\NI. G. J.. F. H. IOL (if" ANI) . L. MIYERHOFI-, AC I. imin. (,,/i

r, ,,-ro I'I/uIrx X,11,At
I, r,'I ,
to( i o'i . PtHARMACOL BIOCHEM BFHAV 32Q) 25-561. l9A. - ihc preselti experiment was
ckitndulCed to determine %khetherthe plasma hormonal and pituitarN cyclic AMP responses obcrtsCd following a single
c\poisttre to an acute stressor %soulddiminish 'ollowing reexposures to the same stressor. Fifteen-min stress exposure',
I forced running) kscrc separated by 45-min ecovery periods. Separate groups of control and stressed animals %%ere
sacrificed betore and after each of foUr 15-min stress periods and after each recoverx period. 1he first cxpoure to IS min
ot' orced running raiked plasma ACTH. corticosterone and pituitary cyclic AMP levels approximatelk 6-fold and more than
tripled lev els of plasma piolactin. Plasma ACTH and pituitar cyclic AMP responses to the second. third and fourth stress
e\posures vserc %er similar to the responses to the first stress exposure. and levels of these substances returned to
prcstres levels during each 45-min recover}y perod. Plasma prolactin responses to the fotr stress sessions wvere somev hat
Sariable bitt no significant trend among the responses was seen. Plasma prolactin levels also returned to prestress leels
betmeen stress exposures. Corticosterone levels were similar following each of the four stress sessions btt levels remained
ie\ ated compared ioprestress levels between stress exposures. These data suggest that pituitar, responses to acute stress
are rapid. that return to prestress levels i,also rapid. with the exception of corticostCrone. and that repeated responses of
the same magnitude may be evoked when stressors are separated by short recovery periods.

A(" H Corticosterone Prolactin Pituitary cyclic AMP Stress Rat -

ACUTE stress activates a multitude of neuronal and hor-
monal responses (9. 12. 27. 32). The peptide corticotropin
releasing factor (CRF) isolated and characterized bv Vale
and colleagues appears to play a key role in both autonomic
and hormonal responses to acute stress 5. 10, 19, 33). CRF
appears to be the primary regulator of ACTH release from
the anterior pituitary gland, although other secretagogues
including norepinephrine. vasopressin and angiotensin Ii
may also affect ACTH release (6. 26. 30). CRF. released into
the pituitary portal circulation, binds to specific CRF recep-
lors located on corticotroph cells of the anterior pituitary.
Binding initiates a sequence of events including stimulation
of adenylate cyclase. synthesis of cyclic AMP, activation of
cyclic AMP-dependent protein kinase and stimulation of re-
lease and synthesis of ACTH (2. 3. 20). Both in vitro and in
vivo studies have suggested that pituitary CRF receptors
may desensitize fbllowing either continuous in vitro ex-
posure to CRF or repeated in vivo administration of exogenous
CRF such that less ACTH release is seen in response to CRF
(28. 29. 34). The present experiment was conducted to deter-
mine whether desensitization to naturally-evoked pulses of
CRFwould beobserved invivo. Repeated exposure toanacute
stressor was used to stimulate CRF release. Pituitary cyclic
AMP and plasma ACTH responses were used to gauge the
sensitivity of the CRF receptors. Plasma prolactin, which is not
regulated by CRF,was measured as an independent estimate of
the "stressfulness*" of each stress challenge since it was
possible that a behavioral habituation to the stressor would de-
velop. ACTH regulates adrenal corticosterone release and
this stress-responsive hormone was also measured.
METHOD
Male Sprague-Dawley rats (275_25 grams) were purchased
from Zivic-Miller and housed for 2 weeks prior to the exper-
iment in a light and temperature-controlled housing area.
The rats were individually caged with food and water free

Resear.h was conducted in compliance v ith the Animal Welfare Act. and other Federal statutes and regulations relating to animals and
experiments ti olving animals and adheres to principles stated in the Guid.or t/ (ct, ore iotU, of Lalrortirr Animal. N IH publication
X5-23. All procedure, were reviewed and approved by the WRAIR Animal Use Review Committee.
- she of the atithorfs) do not purport to rellect the position of the Department of the )eltense (para 4-3. AR 360-5).
wies',

89 9 U,.
,0
-0 "
 KANT. M(OUGFY ANI) MLYRI-O(FF

r320

5. T 280

- 240

3 4.0 200
-' 160

-i 3.0-, 20

E 80

2.0- 40

0 30 60 90 120 150 180 210 240

1.0 TIME (min)

FIG. 2. Plasma ACTH response to repeated stress (sec Fig. I for

further details). *Significantly different from control. I- 0.(t5.
I I I I I I l I I 1 I

30 60 90 120 150 180 210 240

TIME I'mim) 3 or 4 running sessions with or without a 45-min recover\

(.. Pituitary . lieAMP response to repeated stress. A total or"
81)rats %ere used in this experiment including 16 control and 64
experimental. Each point represents the meant SEM of 16 controls
or 8 stressed rat,.Stressed rats were exposed to from I to 4
fifteen-mn stres sessions - a 45-min recover, period prior to SKc-
rifice. Significantl different from control, - 0.05.
available. Lights were on from 0600 to 1800 hr daily. The
experiment described was conducted during 4 consecutive
mornings so that all animals could be sacrificed within a 2-hr
period (0950 to 1150) to avoid significant circadian variations
in hormonal and pituitary cyclic AMP responses to stress
113). Four control animals and two animals from each of the
eight experimental groups were sacrificed each of the four
days Control (nonstressed)
days. Contlro rats were sacrificed
tnhneroed rawe within
sacrinimizeonificdI min
withitional
ot removal trom their home cage to minimize nonspecific
stress. Experimental animals were sacrificed either im-
mediately after a 15-min stress session or 45 min following
nd o a tresbelw).between
thesesion(se
the end of a stress session (see below),
IE.xpe'rimental Protur,,c'
Control rats were sacrificed by decapitation using a guil-
lotine immediately upon removal from their home cage.
Stressed rats were exposed to from one to four sessions of
''forced running" (I I. 14. 17. 18). Rats were placed in
motor-driven metal mesh wheels (diameter 38 cm: 6 rpm, a
fast walking speed) for fifteen min. Rats were either sac-
rir:ced immLJiatdly f,:,iiig a stress session or placed back
in their home cage for a 45-min recovery period. Some rats
were sacrificed after each recovery period and others were
placed bck into the wheel for another 15-min stress session.
Thus, nine separate treatment groups were compared: con-
trol (no running), and separate groups of rats exposed to 1,2.
period prior to s,-rificc. Pituitaries were removed, weighed
and immediately placed into 90C sodium acetate buffer (pH
6.2, 0.05 M) for 15 min to inactivate pituitary enzymes and
prevent post-mortem changes in levels of cyclic AMP (211.
In order to minimize the time required prior to heating the
pituitary tissue, the anterior pituitary was not dissected free
from the remaining tissue. However. we have previously
shown that stress-induced increases in pituitary cyclic AMP
occur in the anterior but not posterior lobe (25). Following
sonication and centrifugation. supernatants were stored at
-40-C until assayed for cyclic AMP. Trunk blood was col-
lected in heparinized beakers: Trasylol (a peptidase in-
hibitor) was added and plasma was stored at -40 C until
assayed for ACTH. prolactin and corticosterone.
,4.s oavx.
Materials for the prolactin assay wert provided by the Na-
Institute of Health through the Rat Pituitary Hormone
Distribution Program. Prolactin was radioiodinated as previ-
ousyrib ed (22). Witin as varioin as prevan
ously described (22). Within assay . variation was <me: and
assay variation <12'/ Corticosterone was meas-
ured by radioimmunoassay using an antibody produced in
our laboratory against corticosterone-2 I -hemisuccinate: BSA.
Somogyi reagents were used to separate free from bound
ligand (24). Corticosterone Il,2-'H(N(, specific activity 50
Ci/mmol. New England Nuclear] was the labelled ligand.
Assay sensitivity was 0.6 /gC/l. The intraassay and interas-
say coefficients of variation were 6% and 12%4 respectively.
ACTH was measured using a radioimmunoassay kit (Ir-
muno Nuclear Corp). The assay was performed in 12x75
polypropylene tubes using an overnight incubation at 4'C.
Assay sensitivity was approximately 10 pg/ml. The intra-
assay coefficient of variation was 2.5% at 380 pg'ml and the
interassay coefficient of variation was --51%.Cyclic AMP
was measured by radioimmunoassay using antibodies char-
acterized in our laboratory (22).
HoR\l( )NA\I R[SPONSES TO RFPFAT|ID STRESS

20 36

18
T
32 -
16- *-*
C= 28 -**
14,14-
_ -S 24
S"' 12 - T
NF ;Z 20
I-z 10- T LI.' F

16

I
,C-,

i L8 30 0 90126 50 10 21 24

2 I\, I I I

I_ __
_ __ __ __ __0 3U 6a 90 12', 150 180 210 240
0 60 120 180 240 TIME (min)
TIME (min)
FIG. 4. Plasma corticosterone response to repeated stress f see Fig. I
FIG. 3. Pla,ma prolactin response to repeated stress (see Fig. I for for further details). *Significantly different from control. I <1.0 5.
fturther detaiki Sigriticantl,, different from control. p 1.05.

.'htli
tjis DISCUSSION

Data o,crc analy zed by one-way analysis of variance. Fol-
IoNing the finding of a significant F score. follow-up corn-
parisons v ere made for each group vs. control. Differences
%%ereconsidered to be significant at P<0.05.
RESULTS
As shown in Fig. I. acute stress markedly increased
levels of pituitary cyclic AMP. Forty-five min following the
first 15-min stress exposure. levels of pituitary cyclic AMF
had returned to prestress levels. Pituitary cyclic AN - -
sponses to the second. third and fourth stress sessio, crc
similar to the first response and levels returned to bas,
between each stress session
ACTH responses to stress mirrored the pituitary cyclic
AMP responses as shown in Fig. 2. Again, no diminished
ACTH response was seen following repeated stress expo-
sures and levels of ACTH returned to prestress levels (luring
each 45-min recovery period,
Plasma prolactin responses were somewhat variable (Fig.
3). More importantly. since prolactin response was used in
this experiment to detect possible behavioral adaptation to the
stress stimulus, no pattern of decreasing response was seen
with increasing numbers of stress exposures. Prolactin levels
also returned to prestress baselines during each recovery
period,
Plasma corticosterone levels increased greatly following
the first stress exposure and then failed to return to baseline
during the first recovery period (Fig. 4). Levels ofcorticoste-
rone immediately following exposures to subsequent stress
sessions were similar to the first response, but levels of cor-
tic,..crone after cach 45-min recovery period decreased for
each of the first three exposures.
The results of this experiment confirm other studies from
our laboratory (13. 15. 16, 23) which have shown that
stress-evoked release of ACTH is closely linked to observa-
bt e i-.creases in levels of pituitary cyclic AMP. Both these
responses are thought to be mediated via stress-induced re-
lease of CRF and its subsequent action at the pituitary cor-
ticotroph.
Regulation of the release and synthesis of ACTH from the
anterior pituitary corticotroph has been shown t. 1L aa
plex process. Not only do numerous secretagogues influ,nce
ACTH secretion tnder normal physiological status, but the
relative importance of these compounds may change follow-
ing disruptions of homeostasis. e.g., adrenalectomy (7). In
addition. corticosterone. regulated by ACTH. feeds back
upon both the brain and pituitary gland to affect the release
and synthesis of ACTH (1,4. 8).
Data from other laboratories have shown that continuous
in vitro exposure to CRF or repeated administration ofexog-
enous CRF or continuous exposure to stress in vivo results
in decreased responsiveness of pituitary corticotroph recep-
tors to CRF as measured by ACTH release (28, 29, 31. 34).
In the present experiment we examined two indices of CRF
receptor-stimulated function, pituitary cyclic AMP accumu-
lation and ACTH release. We measured the response-
recovery-response capabilities of this system and found that
repeated full responses are seen when a recovery period is
allowed between presentations of stressors. Desensitization
of CRF receptors to acute stressors in vivo appears to be
a short-lived phenomenon. Thus, the organism can respond
fully to new stress challenges.
The more rapid rate of recovery of corticosterone levels
toward baseline values fol'iwing more exposures to the
 KAN. NIOLGIIY ANID MIFYFRHOFI:

It IresOr as coilplrexl to thle ce'%atexl:1-

oi costeronlex elNCS at
he en kit'o the first re:ox cr\ Period Could be iterpretled as
ictlec:tinz a Shorter duration oft ACt H release xxith repeated
'tressor Presentation and thus a siizn of desensitization.
Doss ever. xxe feel that the elev.ated corticostcrone seen at
th is point is more likeir to he associated xxith mild xrsscocort
ec.g.. noise. mlovement) continingng g h eoex
period \%hieh xxas habituated ito as the experiment progressed
hrough Subsequent Stress and rcovers sessions. A longer
duration of' A\C11H release %W uld also has e resulted in a
larger amprlitude oft plasnlit ACIYH at the 15 min mea sure-
lient . Since cortiCOSMerone leel couIld also he affcted h\
si ress-indUneed changes inl adre nal sen ssitits to ACt H or
changes in corticoster[One clearance rates. wxe beliexe that
the raost dirct inxlic, of c-orlicotropo iespouse nicasured in
this experintent itre the plaisnt~ A(' I I and pituitar\ cyclie
A NIP levels. these measurements do nol show anm deseni-
sit i/at ion to repeated !i leCssor presentation.
Since corticosterone levels remained e ated during the
first rcoverN period without attenuating the ACTH re-
sponse to the second stressor. the inhihitory role of gtu-
icoids onl ACTH release inl this pat tern of' st ressor
presentation appeared to be negligible. Further studies of the
regulation of this systemn under conditions, of acute. repeated
and chronic Stress are underss ay in our- laboratory
Mt IN )I tIMF t(MN
- tIS
tlie auithor' appreciate ihe experi technical support pros ied h%
(tini Wornflex Witlie Ga~mble. Golden Dris er. Clsdtc Kenio'. SCGI
(jrril Fields. terence Fggtesion and Angeta Brossn and ihe sekretar-
iail tippoit of llrenda NMesser and Karen D~aniels.

R E FE RF'N ( FS

\h,,t.S~tmi-. iti IS J- Aguilera. Gi. lBiphasic inhibition of t13.Kant. G, i.: Mouge. . I.: Me\xerhoff. J. L. Diurnal \ -iriation
.idicn io in.toi 1elease bs corticosterone in cultured in neuroendocrine response ito Stress in rats: Plasma AC [H.
is :clls. Fnidocrinology 119:972-97: 1986.
,WrICrlII p111L1II /3-endorphin. /3--.1H, corticosterone. prolactin andl pituitary
\1'111ILG(i . H ussood . J P.: Wiltn. 3. V. Niorcill-j:roo ii. cyclic AMNIP responses,. Neu-roetidoeCrinOlogv 43:183- 390: 1986.
.1 1t. (it K .1. Mtechanismn t*of ictitu o t'rto~ic:Tirill- 14. Kant. G. J.: Mexerhoff'. J. L.: Bunnell. 13. N.: Leno\. R. H.
and other jcutiti t
!eatC'ictor in~I ooipiil releaseC nl Cyclic AMIP and execlic GM P response io stressN in brain and
5
Tat piltt rs cclls. .1 li'l (hmliil s Slili Sii4 11W, pitlitiar\ : StreCss elevates pituitar\ csclic A-MP. Pharmacol.
3.Antoni F.NA s pi~othalaii '011ttt1 1t .tdIC111 lt11ti01tttpill Blitchem. Itehax . 1'71067-10172: 19N2.
'ecretton- \dx ncc, '11inct!le i.'esol .41I-teidite 1. Kanit (iG.I .: (leshanskx . MI.:Walc/ak. 1). ID.: MIoes. F.
Iirtet
tropin disaini. i [ndtici Re,
It - 1 1>- 198t, H.: NieserhoffI. J. L. Comparison of the effects oif CRF and
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corttcotropinicle.,Iit iteli-ind tCed ptodulCtion ot adcnoinc- mio. Psvehiatrv Res- t61(Suppl. 4):64: 1986.
.- monophtspnhtte IT ,itl1tined ,intcrior-plitiil\ cells. Fudo- 16. Kant. G. J. : ()leshansk M. :Walczak. 1). 1). Mouge\ . F.
II :65 -602: 1983
11noie H., Mcverhoff. J1.L. Comparison of the effec:ts of' CRF and
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111:928-911: 1982.' Pennington. L. L.: Meyerhoff. J. L. Comparison oif stress re-
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:iss~t to sttix% the regulation of* anterior lobe adrenocorticotro- plasma prolactin. grow th hormxone and croticosterone.
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-. lallman. NI. F.: Nhikara. G. B.: Roberts. J. L. : Levin. N.: Stress is stressor specific. Pharmacol. Biochem. Bchas.
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