Physiology & Behavior 68 (1999) 47–53
0031-9384/99/$ – see front matter © 1999 Elsevier Science Inc. All rights reserved.
Corticosterone response to the plus-maze: High correlation with
risk assessment in rats and mice
R.J. Rodgers, J. Haller, A. Holmes
Ethopharmacology Laboratory, School of Psychology, University of Leeds, Leeds LS2 9JT, UK
Institute of Experimental Medicine, H-1450 Budapest, P.O. Box 67, Hungary
School of Biological Sciences, University of Wales Swansea, Singleton Park, Swansea SA2 8PP, UK
Received 31 March 1999; accepted 14 July 1999
, J. Halasz
, T.J. Walton
, P.F. Brain
Exposure to the elevated plus-maze induces behavioural and physiological effects in rodents consistent with fear/anxiety. Maze-naive
animals display high levels of risk assessment towards the open arms, and explore these areas less extensively than other parts of the maze
while, immediately following the test, pain latencies, skin conductance levels, and plasma corticosterone titres (CORT) are significantly
elevated. Although previous research has suggested a link between the plasma CORT response and open-arm exploration, significant el-
evations in CORT have also been found with restricted exposure to the closed arms. The present study employed ethological measures in
an attempt to further characterise the relationship between behavioural and CORT responses to this widely used animal model of anxi-
ety. Our results confirm that, relative to home-cage controls, 5-min exposure to the plus-maze significantly increases plasma CORT levels
in test-naive male Wistar rats and male Swiss–Webster mice. Furthermore, in both species, the CORT response was found to be highly
correlated with measures of risk assessment (mice:
time), general locomotor activity, rearing, or head dipping. Findings are discussed in relation to the functional significance of risk assess-
ment in potentially dangerous situations and the potential involvement of glucocorticoids in this process.
All rights reserved.
0.58), but not with measures of open-arm activity (entries,
© 1999 Elsevier Science Inc.
Elevated plus-maze; Plasma corticosterone; Stretched-attend postures; Risk assessment; Rats; Mice
The elevated plus-maze is one of the most widely used
models for the study of anxiety-related processes in animals
[1–3], and has been validated for both rats  and mice .
In this test, anxiety is typically measured by indices of
open-arm avoidance and general locomotor activity by the
frequency of closed-arm entries (e.g., [5–7]). More recently,
behavioural scoring has been extended to include a variety
of specific acts and postures which, incorporated into more
comprehensive factor analyses, have revealed additional di-
mensions to plus-maze behaviour patterns, for example,
vertical activity, directed exploration, decision making and
risk assessment [6,8–13]. Inclusion of these ethological
measures permits comprehensive drug profiling in the
maze, thereby facilitating the identification of behaviourally
selective actions . Furthermore, measures of risk assess-
ment (primarily, stretched-attend postures) have proved ex-
tremely valuable in identifying anxiolytic-like actions of
drugs (e.g., 5-HT
receptor ligands) not detected by con-
ventional scoring methods (e.g., [14–16]).
Physiological confirmation of the aversive or stressful
effects of plus-maze exposure is provided by evidence of
posttest elevations in pain latencies (e.g., ) and skin con-
ductance levels . Furthermore, consistent with the ef-
fects of various physical and psychosocial challenges (for
review, see [18,19]), exposure to the plus-maze produces a
significant increase in plasma corticosterone (CORT) titres
[4,20–24]. Although this response is greater following con-
finement to an open arm , closed-arm confinement also
increases CORT levels relative to home-cage controls
[4,21]. Although these data suggest that a novelty-induced
CORT response to the plus-maze is exacerbated by forced
exposure to the more aversive open arms, they do not clarify
the relationship between CORT and spontaneous behaviour
in this test. The aim of the present study was to address this
* Corresponding author. Tel:
R.J. Rodgers et al. / Physiology & Behavior 68 (1999) 47–53
issue by exploiting the behavioural detail provided by etho-
logical analysis [2,3]. Furthermore, in view of possible spe-
cies differences, the work involved parallel studies on mice
and rats conducted, respectively, at the University of Wales
Swansea (UK), and the Institute of Experimental Medicine
2. Materials and methods
Subjects were adult male Swiss–Webster mice (25–33 g,
supplied by Bantin & Kingman, Hull, UK), and adult male
Wistar rats (350–400 g, supplied by Charles River, Buda-
pest, Hungary). Animals of both species were group housed
(mice: 10/cage, 25
13 cm; rats: 6/cage, 50
20 cm), and maintained in temperature (mice: 21
C) and humidity (mice: 52
10%)-controlled environments under 12 h reversed-light cy-
cles (mice: lights off, 0700 h; rats: lights off, 1100 h). Food
and water were freely available, with the exception of the
brief test periods.
2%, rats: 60
2.2. Apparatus and procedure
Rat and mouse elevated plus-mazes, as well as the asso-
ciated test procedures, were based on those previously vali-
dated and now routinely used in the collaborating laboratories
(mice: , rats: ). The mouse plus-maze comprised
two open arms (30
0.25 cm) and two enclosed arms
15 cm) that extended from a common central
5 cm). The apparatus was constructed from
black (floor) and clear (side and end walls of closed arms)
Plexiglas, and was elevated on a wooden pedestal to a
height of 60 cm above floor level. Open-arm exploration
was encouraged by the inclusion of a slight raised edge
around their perimeter (0.25 cm) and by testing under dim
red light (4
60 W indirect). The rat plus-maze comprised
two open arms (50
20 cm) and two enclosed arms (50
30 cm) that extended from a common central platform
20 cm). The apparatus was made from wood (painted
dark grey), and elevated to a height of 80 cm above floor
level. Testing was conducted under dim red illumination (1
40 W, indirect).
All testing was conducted during the dark phase of the
light/dark cycle, and commenced with the placement of sub-
17) on the central platform of
the maze facing either an open (mice) or closed (rats) arm.
A conventional test duration of 5 min was employed for
both species and, in each series, the maze was thoroughly
cleaned between subjects. Mouse sessions were recorded on
videotape for subsequent analysis, while rat sessions were
scored live from a videosignal relayed to a monitor in a
nearby room. Immediately following testing, subjects were
transported to an adjacent laboratory where they were killed
by rapid decapitation, and trunk blood was collected. Con-
trol blood samples were collected from subjects of the same
age/housing conditions (mice:
directly from their home cages.
2.3. Corticosterone assay
Trunk blood was collected in polypropylene tubes con-
taining citrate anticoagulant, centrifuged for 5 min at room
temperature, and stored at
assay, CORT was displaced from corticosterone binding
globulin (CBG) by heating samples to 60
agents (Amersham Life Science Limited, UK) were placed
into tubes in duplicate: standards (0.078–200 ng corticoster-
one in 100
L) contained 100
L rabbit anticorticosterone serum, and test samples
L total serum volume
I-corticosterone. All tubes were
thoroughly vortexed, covered, and left to incubate for 2 h at
room temperature, following which 400
second antibody reagent was added and left to incubate for a
further 10 min. The antibody bound fraction was magneti-
cally separated for 15 min, supernatant discarded, and tubes
allowed to drain for 5 min; radioactivity in each tube was
-scintillation counting for 60 s. The sensi-
tivity of the assay was 0.2 pmol, and CORT levels were ex-
pressed as ng/mL plasma.
C until analysed. Prior to
C for 30 min. Re-
L rabbit anti-
Trunk blood was sampled on ice-cold EDTA-containing
plastic tubes, and stored at
was performed in duplicate, and plasma CORT levels mea-
sured by radioimmunoassay [25,26]. Prior to assay, CORT
was separated from CBG at low pH (200
acid; 1-h incubation at room temperature). Antiserum was
raised in rabbits against corticosterone carboxymethyl-
oxime bovine serum albumin (prepared at the Institute of
Experimental Medicine, Budapest), and
carboxymethyloxime-tyrosine-methyl ester (Isotope Insti-
tute Ltd, Budapest) was used as tracer. Eight CORT solu-
tions were used as standards (0.2 pmol/10
L), and test samples contained 10
L CORT standard, 100
tracer. Following the addition of cold polyethyleneglycol
and incubation for 3 h at 4
C, samples were centrifuged at
C and radioactivity measured in the deposits. The sensi-
tivity of the assay was 1 pmol, and CORT levels were ex-
pressed as ng/mL plasma.
C until analysed. The assay
L 0.1 mol citric
L total serum volume
L antiserum, and 200
2.4. Behavioural analysis
Behaviours were scored by highly trained observers (in-
0.90) using ethological analysis soft-
ware (mice: ‘Hindsight’ ; rats: ‘EthoVision,’ Noldus,
The Netherlands). Scoring was based on measures validated
and routinely used for the two species in the UK (mice:
) and Hungarian (rats: ) laboratories.
For mice, behavioural parameters comprised both con-
ventional spatiotemporal and more recently developed etho-
R.J. Rodgers et al. / Physiology & Behavior 68 (1999) 47–53
logical measures . Conventional measures were the fre-
quencies of total, open and closed entries (arm entry
four paws into an arm), % open entries [(open/total)
and % time spent in open, closed, and central parts of the
maze [e.g., (time open/session duration)
cal measures comprised frequency scores for rearing (verti-
cal movement against the side and/or end of the walls; N.B.
mice very rarely exhibit unsupported rearing), head dipping
(exploratory movement of head/shoulders over the side of
the maze), and stretched-attend postures (SAP: exploratory
posture in which the body is stretched forward then re-
tracted to the original position without any forward locomo-
tion), as well as total duration scores in seconds for rearing
and grooming (licking, scratching, and washing of the head
and body). In view of the importance of thigmotactic cues to
rodent exploration in the plus-maze (e.g., ), head dipping
and SAP were also differentiated as a function of their oc-
currence in different parts of the maze. Thus, the closed arms
and centre platform were designated as “protected” areas
(i.e., offering relative security) and the “percent protected”
scores for head dipping and SAP calculated as the percent-
age of these behaviours displayed in or from the protected
areas (e.g., [(protected SAP/total SAP)
For rats , conventional behavioural parameters (re-
corded automatically) were the frequency of open-, closed-,
and total arm entries (arm entry
an arm), the ratio of open-arm entries (i.e., open/total), and
the percentage of time spent in the open arms [(time open/
100]. Ethological measures, recorded
manually using the event-recorder facilities of Ethovision,
were protected head dipping (investigating over the sides of
the maze) and protected stretched-attend postures (SAP; in-
vestigating open arms from the central platform or a closed
arm). Both behaviours were recorded as frequencies and du-
rations, with the latter expressed in terms of percent time
spent engaged in their display [(time in seconds/session du-
middle of the animal in
As appropriate for the characteristics of the respective
datasets, comparisons between plasma CORT levels in
home-cage controls and plus-maze–exposed animals were
performed by the Mann–Whitney
-test (rats). Relationships between plasma CORT
levels and behavioural measures were examined using
Spearman’s Rank-Order correlations.
-test (mice) and inde-
Experiments conducted in the UK were performed under
licence in accordance with the Animals (Scientific Proce-
dures) Act 1986, while those conducted in Hungary were
performed in accordance with the Helsinki agreement on
The behavioural profiles of Swiss–Webster mice and
Wistar rats are summarised in Table 1. In both species, 5-min
exposure to the elevated plus-maze produced significant in-
creases in plasma CORT levels in comparison to home-cage
controls: mice: control median
21.3 (12.8–23.7) ng/mL,
12.3 mg/mL, exposed 227.2
0.01. Correlations between plasma CORT lev-
els and individual plus-maze parameters are summarised in
Table 1 and Fig. 1. For mice, significant correlations were
obtained only for percent protected SAP (
and % closed-arm time (
the only significant correlation observed was for % time
spent displaying protected SAP (
8.5 (range 2.6–18.6) ng/
0.05; and rats:
0.03) while, for rats,
Present results confirm that test-naive Swiss–Webster
mice and Wistar rats not only avoid the open arms of an ele-
vated plus-maze but also display a range of other behav-
iours including rearing, head dipping, and stretched-attend
postures (e.g., [11,18]). However, despite these basic simi-
larities, there are some notable differences, for example, al-
Correlations between plasma corticosterone levels and plus-maze
behaviours in male Swiss–Webster mice (
(n ? 17)
n ? 9) and male Wistar rats
Total arm entries
% Open entries
% Open-arm time
% Closed-arm time
% Centre time
% Protected head dips
% Protected SAP
Total arm entries
Ratio open entries
% open-arm time
% closed-arm time
% centre time
Head dips (frequency)
% Time head dipping
% Time protected SAP
17.67 ? 1.67
6.89 ? 0.82
10.78 ? 1.04
38.64 ? 2.84
20.19 ? 2.39
19.55 ? 2.03
60.26 ? 3.69
7.89 ? 2.12
3.65 ? 1.18
12.00 ? 1.85
76.54 ? 4.72
14.56 ? 1.68
70.79 ? 4.83
1.56 ? 1.03
?0.72, p ? 0.03
0.87, p ? 0.01
10.58 ? 1.86
3.11 ? 0.84
7.47 ? 1.12
0.23 ? 0.04
3.95 ? 1.63
82.60 ? 3.29
13.41 ? 2.53
4.29 ? 0.76
2.45 ? 0.55
12.70 ? 1.24
9.77 ? 1.05
0.58, p ? 0.02
Behavioral data are expressed as mean values ? SEM. SAP ?
stretched attend posture.
R.J. Rodgers et al. / Physiology & Behavior 68 (1999) 47–53
though displaying similar absolute levels of SAP, rats
showed a stronger aversion to the open arms (% time open)
as well as lower levels of locomotor activity (closed and to-
tal arm entries) and directed exploration (head dipping).
Furthermore, although both species clearly avoided the
open arms, mice spent the greater proportion of their time
on the centre platform, whereas rats spent most of their time
in the enclosed arms. These rat–mouse differences are
rather similar to those previously reported for Long–Evans
rats and Swiss–Webster mice tested in a visible burrow situ-
ation [28,29]. Thus, when briefly exposed to a cat, rats re-
treated to the tunnels (where they showed high levels of
freezing) whereas, following initial flight, mice persistently
returned to tunnel openings where they displayed high lev-
els of risk assessment. Although consistent with a possible
species difference in defensive strategy, marked strain dif-
ferences in the plus-maze profiles of both species  would
urge caution in interpreting present data in terms of a simple
In agreement with previous findings [4,20–24], and rela-
tive to home-cage controls, brief exposure to the plus-maze
resulted in a significant elevation of plasma CORT levels in
both species. Furthermore, the CORT response of both spe-
cies was remarkably similar in magnitude, i.e., relative to
conspecific home-cage control values, the percent CORT
increase was approximately 151% for mice and 153% for
rats. Nevertheless, it is obvious that control CORT levels
were markedly different for the two species (8.5 ng/mL for
mice versus 89.9 ng/mL for rats). This discrepancy cannot
readily be attributed to differences in housing conditions
(group housing for both species), light cycle (reversed for
both species), time of sampling (early–middark phase for
both species), sampling method (rapid decapitation for both
species), handling (minimal for both species), or exposure
to distress vocalisations/odours (in both cases, animals were
sacrificed in a location entirely separate from holding rooms
and behavioural laboratories). However, while the CORT
assays employed were very similar in most respects, differ-
ences in the method used to separate CORT from CBG (for
mice, heating; for rats, lowering of pH) may have at least
partially contributed to the observed discrepancy in basal
values. In this context, it is important to note that the exist-
ing literature confirms wide variation in control CORT val-
ues for both species, but offers no clear explanation for such
differences. Thus, control values ranging from ?10 mg/mL
to ?300 ng/mL (e.g., [4,20,22,23,30,31,32,61]) and from ?5
ng/mL to ?40 ng/mL (e.g., [7,33–35]) have been reported
for rats and mice, respectively. As such, the home-cage con-
trol values recorded in the present study are not in any way
atypical of previous findings and, although very different
for the two species, clearly permitted the detection of statis-
tically significant increases in steroid levels in response to
In their now classic article on the validation of the plus-
maze as a model of anxiety in rats, Pellow and colleagues
 reported that confinement to either an open or an en-
closed arm of the maze produced a significant increase in
plasma CORT relative to home-cage controls. However, in
support of behavioural observations indicating a stronger
emotional response to the open arms, the CORT response to
the open arm was significantly greater than that to the en-
closed arm. Nevertheless, plasma CORT levels were signif-
icantly increased in response to the closed arms per se (see
also ), while, in the present study, a similar response
was evident in Wistar rats following a free exploration trial
characterised by very low levels of open-arm exploration.
Such observations suggest a relationship between this endo-
crine stress marker and a behavioural response other than
open arm activity per se. In agreement with this inference,
present results failed to show (for either species) a signifi-
cant correlation between plasma CORT levels and any mea-
sure of open-arm exploration. It should perhaps be noted
that although a correlation of ?0.52 was observed between
CORT and % open-arm entries (mice), this was neither sta-
tistically significant nor supported by a low negative corre-
lation (?0.32) for % open-arm time. Furthermore, the
CORT response did not correlate with indices of general lo-
Fig. 1. Correlations between risk assessment and plasma corticosterone
response to the elevated plus-maze. (A) Percent protected SAPs and
plasma corticosterone levels in maze-naive male Swiss–Webster mice (n ?
9); and (B) percent time in protected SAPs and plasma corticosterone
levels in maze-naive male Wistar rats (n ? 17). SAP ? stretched attend
R.J. Rodgers et al. / Physiology & Behavior 68 (1999) 47–53
comotor activity (closed entries), vertical activity (rearing),
or directed exploration (head dipping). Rather, for both spe-
cies, CORT levels correlated highly and positively with
stretched-attend postures (SAP). In neither instance, how-
ever, did this correlation involve the absolute frequency of
SAP; for mice, it specifically involved the proportion of
SAP displayed in or from protected areas of the maze and,
for rats, the proportion of time spent in protected SAP di-
rected specifically towards the open arms. As such, they key
behavioural association with the CORT response to the
maze appears to be aborted attempts to enter the open arms
rather than actual exploration of these potentially more dan-
gerous/threatening parts of the apparatus. The additional
(though negative) correlation observed in mice (but not rats)
between CORT and % time spent in the closed arms (rela-
tive safety vs centre platform and open arms) may relate to
the already noted difference in the spatiotemporal prefer-
ences displayed by the two species.
The stretched attend posture (SAP) was first documented
by Grant and Mackintosh , who referred to “stretched
attention” as an ambivalent behaviour (i.e., reflecting ap-
proach–avoid conflict). It has subsequently been identified
and further characterised in a variety of threatening situa-
tions, including social, predatory, and nonsocial contexts
[28,29,37,38]. On the basis of their elegant studies on anti-
predator behaviour in rats, Blanchard and Blanchard 
interpreted SAP in terms of “risk assessment,” i.e., informa-
tion-gathering behaviours displayed in potentially threaten-
ing situations, the function of which is to optimize the most
adaptive behavioural strategy (see also ). Consistent
with this view, subsequent research has shown that risk as-
sessment measures, and SAP in particular, are very sensi-
tive to the effects of anxiolytic and anxiogenic drugs (e.g.,
[15,16,40–44]). As such, present data would be consistent
with a strong positive relationship between CORT and risk
assessment in rats and mice exposed to the plus-maze.
Recently, McNaughton  has proposed a hippocampal
hyperactivity model of anxiety-related disorders in which
the hippocampus is seen as playing a critical role in risk as-
sessment. As this structure is a major CNS target of CORT
(for review: ), the strong association between CORT
and risk assessment in the plus-maze may reflect steroid fa-
cilitation of information-processing (and, thus, learning) in
novel and potentially dangerous environments. In this con-
text, it is already known that spatial learning occurs very
quickly in the plus-maze. Thus, an initially high level of risk
assessment and an absence of open/closed preference rap-
idly (i.e., within 2–3 min) gives way to much lower levels of
risk assessment and unambiguous open-arm avoidance
[11,47,48,49]. In view of this temporal pattern, however, it
seems somewhat improbable that the currently observed
correlations between CORT and risk assessment reflect an
activating influence of the steroid on information gathering.
First, CORT measurements in the present study were taken
from samples collected 2–5 min after plus-maze exposure,
whereas SAP scores reflect behaviour during the actual test.
Second, while the catecholamine response to stress is fast,
the glucocorticoid response is much slower (e.g. ) and
seems an unlikely mediator of SAP, the highest levels of
which are seen at the beginning of the test. Third, although
exogenously-administered (pharmacological) doses of CORT
have been reported to increase [20,51] or decrease [52,53]
plus-maze anxiety, metyrapone-induced inhibition of CORT
synthesis does not affect open-arm avoidance, suggesting
that endogenous CORT may not be directly involved in me-
diating spontaneous behavioural responses in this test .
Although not completely negating a role for CORT in the
mediation of risk assessment (information gathering), the
temporal dynamics of behaviour and steroid response would
be more consistent with a reverse causal link, i.e., the higher
the level of risk assessment (i.e., the greater the number of
aborted entries onto the open arms), the larger the CORT re-
sponse. In this context, it is pertinent to note that anticipa-
tion of threatening events in humans produces as marked an
elevation in cortisol as the event itself , leading to spec-
ulation that it may be cognitive differences in risk assess-
ment that may distingush subjects who score highly on trait
anxiety . Although the present findings may simply re-
flect the acute homeostatic role of CORT in the face of a
perceived threat , they clearly indicate that this percep-
tion is based not on actual exploration of a dangerous envi-
ronment , but rather, the detection of its existence. Fur-
thermore, in view of growing evidence from animal and
human studies for the involvement of glucocorticoids in
cognitive function [31,56], it is tempting to speculate on the
potential involvement of CORT (and especially its action at
hippocampal GR and MR receptors) in the within- and be-
tween-trials “emotional” learning that is characteristic of the
plus-maze paradigm . Research directed specifically at
this issue may help to resolve some of the already noted incon-
sistencies in the effects of exogenous CORT on plus-maze be-
haviour, the rather puzzling effects of GR and MR antagonists
in different animal models of anxiety (e.g. [57–59]), and the
apparently contradictory behavioural profile in such tests of
transgenic mice with impaired GR-mediated feedback inhibi-
tion of hypothalamic–pituitary–adrenal activity .
In summary, the present study has identified in two spe-
cies a high correlation between the plasma CORT response
to the elevated plus-maze and measures of risk assessment
in this test. The behavioural specificity and robustness of
this relationship is all the more remarkable, given the intrin-
sic methodological differences between the rat and mouse
components of the study. In view of the theoretical impor-
tance of the main finding, further work appears warranted
including 1) replication using fully identical methodologies,
and 2) clarification of the dynamics of the CORT response.
The authors express thanks to the University of Wales
Swansea (School of Biological Sciences) and the University
of Leeds (School of Psychology) for financial support of
R.J. Rodgers et al. / Physiology & Behavior 68 (1999) 47–53
this research. Work in Hungary was supported by OTKA
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