CJP E-prepublication Ahead of Print
Chinese Journal of Physiology 58(×): ×××-×××, 2015
DOI: 10.4077/CJP.2015.BAD335
1
Effects of Escitalopram on a Rat Model of
Persistent Stress-Altered Hedonic Activities:
Towards a New Understanding of Stress
and Depression
Szu-Nian Yang 1, Ying-Hsiu Wang 2, Che-Se Tung 3, Chih-Yuan Ko 2, and Yia-Ping Liu 4, 5, #
1
Department of Psychiatry, Taoyuan Armed Forces General Hospital, Taoyuan 32551
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490
3
Division of Medical Research & Education, Cheng Hsin General Hospital, Taipei 11220
4
Department of Physiology and Biophysics, National Defense Medical Center, Taipei 11490
and
5
Department of Psychiatry, Tri-Service General Hospital, Taipei 11490, Taiwan, Republic of China
2
Abstract
Chronic mild stress (CMS) paradigm is a model to simulate clinical depression induced by longterm environmental stress. The present study investigated the effects of escitalopram, a specific serotonin
reuptake inhibitor (SSRI), on depression-like activities in adult (18 week-old) Sprague-Dawley (SD) rats
that underwent a total 8-week CMS. Body weight, locomotor activity and sucrose consumption of the
rats were measured under CMS paradigm and following escitalopram treatment. The plasma level
of corticosterone was also measured at the end of the experiment. Our results revealed that the CMS
program reduced the body weight, but not the locomotor activity of the rats. Adult SD rats consumed
less sucrose solution under CMS. However, chronic escitalopram regime (10 mg/kg/day for 4 weeks)
appeared not helpful in reversing this CMS effect and, if any, the drug exaggerated anxiety profile of
the animals. Unexpectedly, the stressed rats exhibited higher sucrose consumption than non-stressed
rats after receiving repeated saline injections. Further, the stressed rats were found to have a higher
plasma level of corticosterone after escitalopram treatment. Our results provide an example of the
possibility that previously stressed individuals may develop an anti-depression ability that lessens the
benefits of intervention with antidepressants. Finally, a separate group of rats that entered the CMS
program at 10 week-old were used to examine possible effects of aging to interpret the stress coping
ability observed in the 18 week-old rats. The younger rats developed less anti-anhedonia effects under
repeated saline injections. The data of the present study provide a different perspective on stressinduced depression and possible interaction with antidepressants.
Key Words: anhedonia, antidepressant, chronic mild stress, depression, escitalopram, stress
Introduction
Stress is closely related to mental dysfunctions
in the modern society. Persistent stress can induce
depression (18). It is, therefore, not surprising that
for use as a preclinical approach, the rat model of
chronic mild stress (CMS) has been used extensively
in exploring the environment-induced psychopathologies of depression (23). On the other hand, evidence
also shows that individuals under chronic stress may
develop anti-depression abilities (7), raising a different
interpretation of stress-depression relationship from
Corresponding author: Dr. Yia-Ping Liu, Department of Physiology and Biophysics, National Defense Medical Center, Department of Psychiatry, Tri-Service General Hospital, No. 161, Sec. 6, Min-Chuan East Rd., Taipei 11490, Taiwan, R.O.C. Tel: +886-2-87923100, ext. 18614,
Fax: +886-2-87923153, E-mail: [email protected]
Received: November 14, 2014; Revised: January 27, 2015; Accepted: March 18, 2015.
2015 by The Chinese Physiological Society and Airiti Press Inc. ISSN : 0304-4920. http://www.cps.org.tw
2
Yang, Wang, Tung, Ko and Liu
the perspective of the individual’s reaction to stress.
This is particularly important in terms of the appropriateness of employing antidepressants in the stressrelated mood dysfunctions, given the evidence that the
reported therapeutic effects of selective serotonergic
reuptake inhibitors (SSRIs) have been inconsistent in
the treatment of stress-combined mood disorders (31).
Loss of interest, or namely anhedonia, is one of
cardinal depressive symptoms. Ability of reversing
anhedonia symptom is considered an index for antidepressive effects (21). Previous evidence demonstrated that rodent CMS paradigm had a good face
validity of anhedonia, i.e. reduced responsiveness to
reward, by exhibiting a lower sucrose intake in the
sucrose consumption test (14, 28). However, certain
aspects of using the CMS paradigm are necessary to
be revisited as laboratory protocols may determine
the outcome evaluation of the CMS effects and also
to what degree antidepressants can reverse these effects (36). First, rats prior to entering into the CMS
paradigm are in general housed singly, which may
confound the results obtained, since social isolation
itself induces depression-like activities (6, 10, 32, 39).
Second, the relatively short duration of two weeks of
CMS before the treatment regime, or the drug intervention launched at the same time of CMS, apparently
does not parallel clinical situation in which patients
usually suffer from the stressors long before they can
be treated. Third, the age of rats entering the CMS program is crucial for mediating the drug effects (15);
however, the majority of evidences so far obtained
were from rats entering the paradigm at their preadolescent age (30, 32, 34, 39). Last but not the least,
since rat strain is a determinant for sensitivity of
the CMS model (2), it is interesting to have an idea
of what would happen in rats of lower CMS sensitivity, yet which would endure a longer duration of
CMS.
The present study aimed to clarify the above issues
by examining the CMS effects on locomotor activity
and sucrose consumption in a rat strain with a modest
sensitivity to anhedonia (i.e. SD strain, see 37). Rats
at their adult age were housed in groups and entered
the CMS paradigm for 8 weeks; in the last 4 weeks,
the rats were treated with escitalopram, a quick onset
selective serotonin reuptake inhibitor (SSRI). Finally,
the level of plasma corticosterone of the rats was
measured at the end of the experiment to corroborate
with the behavioral data. Our results may provide a
different and new perspective for stress-induced depression and interactions of such depression with antidepressants.
Materials and Methods
Animals
Adult male Sprague-Dawley (SD) rats (BioLASCO,
Taiwan) arrived at the housing room at 14 weeks of
age, and weighing 250-300 g. The animals were housed
at a constant cage temperature (22 ± 1°C) and humidity (40%-70%). The animals were allowed to
adapt for 2 weeks to the new environment before any
experiments were performed. Rats were housed in
groups of three and were kept under regular lightdark conditions (light on at 07:00 AM and off at
7:00 PM), with food and water available ad libitum,
except during behavioral testing. Considering the
diurnal variation in sensitivity to CMS, the CMS effects on sucrose consumption were tested at the start
of the dark phase (8). The study was approved by the
Institutional Animal Care and Use Committee of National Defense Medical Center.
Experimental Design
Rats at 18 weeks of age (14 weeks at the time of
arrival, 2 weeks for adaptation, and 2 weeks for sucrose
training) were randomly assigned to either the nonstressed or the stressed group (i.e. rats in CMS) for
8 weeks. The escitalopram regime was introduced at
Week 5 and maintained for 4 more weeks. For both
groups, body weight, locomotor activity and sucrose
consumption were measured during the treatment regime. A separate group of rats that entered the CMS
program at 10 weeks of age were used to validate the
aging effects. They received the same CMS program
and were tested for their sucrose consumption after
1 week of saline injections.
CMS
Various unpredictable stressors were presented
for 20 h per day (from 1 PM to 9 AM of the next day)
for 8 weeks. The stressors included food and/or water
deprivation, housing in a cage tilted at 45° with overnight illumination, housing in a cage with soiled and
wet bedding, and individual housing in different cages
with odors. For each day, a single stressor was selected
in a random and non-repeated base. For control, nonstressed rats were used and were placed in the hoarding room without any disturbance.
Locomotor Activity
The locomotor activity test was identical to the
procedure previously used by our team (22). In brief,
the total distance traveled was measured for 30 min
and recorded by a programmed microcomputer (MED
Associates, Albans, VT, USA). The system included
4 plexiglas chambers (43 × 43 × 30 cm 3) equipped
with an I/R array of 16 photodetectors and corresponding light sources that emitted photo beams 3 cm apart
Persistent Stress and Anti-Anhedonia
and 4.5 cm above the chamber floor. Travel distance
was recorded constantly at the assigned intervals and
was controlled by Med-Associates software.
Sucrose Consumption Test
The protocol of sucrose consumption test was
adapted from Wu and Wang (37). A 2% sucrose solution was used to serve as a more potent reinforcer
(1, 26) with a stable pattern of intake (36). Specifically, rats learned that sucrose solution was the only
available source of intake after 18-h deprivation of
food and water. When testing, rats consumed the
sucrose solution at the start of the dark phase for
60 min. The amount of consumed sucrose was obtained by measuring the weight of the bottle after
testing.
Drug
Escitalopram (sponsored by Lundbeck, Denmark)
was dissolved in 0.9% saline solution and was administered intraperitoneally in a volume of 0.1 ml/100 g
body weight. A dose of 10 mg/kg/day was selected
according to a previous study (32).
Plasma Corticosterone
Rats were sacrificed at the end of the experiment
and blood samples were extracted and centrifuged.
Plasma corticosterone was measured using an enzymelinked immunosorbent assay (ELISA) kit following
the manufacturer’s instructions (Cayman Chemical
Company, Ann Arbor, MI, USA). In brief, AChE tracer
and EIA antiserum were added to the wells of the
plate and incubated for 2 h at room temperature on
an orbital shaker. Ellman’s reagent was then added
in the dark for 90 min. The value of corticosterone
was measured using an ELISA reader at a wavelength of 412 nm.
Data Analysis
Statistical analyses of the present study were conducted by SPSS 16.0 for Windows (Chicago, IL, USA).
Data were analyzed by a multiple-way of analysis of
variance (ANOVA) in which STRESS (non-stressed vs.
stressed) and TREATMENT (saline vs. escitalopram)
were between-subject factors. TIME was employed
as a within-subject factor, i.e. repeated measurements.
Tukey HSD method was used for post hoc comparison.
Student’s t test was also used for further analysis
where appropriate. The significance of probability
level was set at 0.05.
Results
3
Regarding body weight, rats in the non-stressed
group gradually became heavier than those in the CMS
group, which was evidenced by the significant effects
of STRESS [F(1,22) = 13.4, P < 0.01], TIME [F(4,88) =
60.8, P < 0.01], and STRESS × TIME [F(4,88) = 56.7,
P < 0.01]. Analysis revealed that simple main effects
existed for STRESS at Week 3 [F(1,110) = 43.2, P <
0.01] and Week 4 [F(1,110) = 40.9, P < 0.01], and
TIME in the non-stressed condition [F(4,88) = 92.8,
P < 0.01], contributed from the bodyweight change at
Week 3 and Week 4 (Fig. 1, upper-left panel). The
CMS-induced bodyweight decrease was restored gradually, as evidenced by a greater weight gain along the
treatment time [F(1,21) = 96.6, P < 0.01, Week 1;
F(1,21) = 5.82, P < 0.05, Week 2; F(1,21) = 40.4, P <
0.01, Week 3], and an effect of TREATMENT × STRESS
[F(1,21) = 5.23, P < 0.05] at Week 3. Further analysis
revealed effects for STRESS in rats that received saline
[F(1,10) = 20.4, P < 0.01] or escitalopram [F(1,10) =
19.0, P < 0.01] (Fig. 1, bar panels).
In the locomotion test, both the non-stressed and
the stressed rats presented a gradual decrease over
TIME in their travel distance at baseline [F(11,242) =
27.9, P < 0.01] and after 4 weeks of CMS [F(11,242) =
69.0, P < 0.01]. Furthermore, there was a main effect
of TREATMENT [F(1,21) = 13.8, P < 0.01], as both
non-stressed and stressed rats traveled longer after
2 weeks of being treated with escitalopram (Fig. 2).
For the sucrose consumption test, 4 weeks of
CMS decreased the amounts of consumption, as evidenced by a significant STRESS × TIME [F(1,22) =
4.84, P < 0.05] and simple main effects for STRESS
in the condition after 4 weeks of CMS [F(1,44) = 12.4,
P < 0.01], and for TIME in rats assigned to the CMS
group [F(1,22) = 25.7, P < 0.01]. Post hoc comparisons
confirmed a strong consumption difference between
stressed and non-stressed rats (P < 0.01) (Fig. 3, left
panel) and the proportion of CMS rats with reduced
sucrose intake was 75%. For sucrose consumption 1
week after drug treatment, significant effects of STRESS
[F(1,21) = 11.1, P < 0.01] and TREATMENT × STRESS
[F(1,21) = 12.0, P < 0.01] were observed. Further
analysis revealed that simple main effects existed
for TREATMENT in the non-stressed rats [F(1,21) =
4.47, P < 0.05], and for STRESS in the rats receiving
saline [F(1,21) = 21.8, P < 0.01] (Fig. 3, middle panel),
indicating the existence of anhedonia in both nonstressed rats under escitalopram treatment and stressed
rats under repeated saline injections. Sucrose consumptions before and after treatment were also compared. Non-stressed rats consumed less sucrose under
saline injections [t(10) = 3.6, P < 0.01], whereas stressed
rats consumed more under escitalopram treatment
[t(10) = 8.2, P < 0.01] (Fig. 3, left and middle panels).
For sucrose consumption 3 weeks after drug treatment,
no effect of STRESS and TREATMENT × STRESS
4
Yang, Wang, Tung, Ko and Liu
Non-Stressed
Stressed
Non-Stressed
Stressed
Weight Gained after Treatment (%)
Body Weight (g)
600
560
520
**
480
**
440
Baseline
1
2
3
120
**
**
Saline
Escitalopram
100
80
60
4
One Week after Treatment
Time after CMS (weeks)
120
**
100
80
60
Saline
Escitalopram
Weight Gained after Treatment (%)
Weight Gained after Treatment (%)
#
120
**
**
Saline
Escitalopram
100
80
60
Three Weeks after Treatment
Two Weeks after Treatment
Fig. 1. Effects of CMS and escitalopram (10 mg/kg/d for 21 d) on the bodyweight of stressed and non-stressed rats. The percentage
(%) of weight gained across the treatments was compared (n = 12 for each group, upper left panel; n = 6 for each subgroup,
bar panels). Values are presented as mean ± SEM; # indicates P < 0.05 vs. saline condition; ** indicates P < 0.01 vs. nonstressed rats.
Non-Stressed
Stressed
Non-Stressed
Stressed
1600
1600
1200
1200
800
800
400
400
0
5 10 15 20 25 30 35 40 45 50 55 60
Time (min)
Baseline befor CMS
0
6000
Total Distance (cm)
Distance (cm)
##
##
5 10 15 20 25 30 35 40 45 50 55 60
Time (min)
After 4 Weeks CMS
5000
4000
3000
2000
1000
0
Saline
Escitalopram
After 2 Weeks Treatment
Fig. 2. Effects of escitalopram on locomotor activity in stressed and non-stressed rats. Data were collected for 60 min and presented
in centimeters of the travel distance in the conditions of baseline, 4 weeks of CMS (for stressed and non-stressed rats, n = 12
for each group, see 2 left panels,), and 2 weeks after treatment (saline or 10 mg/kg/d of escitalopram, n = 6 for each subgroup;
for comparison, layout with bars, see the right panel). The CMS program was still ongoing during the drug treatment stage.
Values are presented as mean ± SEM; ## indicates P < 0.01 vs. saline condition.
5
Persistent Stress and Anti-Anhedonia
#
Sucrose Consumption (g)
30
30
##
25
Non-Stressed
Stressed
**
30
25
25
20
20
15
15
15
10
10
10
5
5
5
**
20
0
Baseline
4 Weeks CMS
0
Saline
Escitalopram
One Week after Treatment
0
Saline
Escitalopram
Three Weeks after Treatment
Fig. 3. Effects of escitalopram on sucrose consumption in stressed and non-stressed rats. Evaluations were executed at conditions of
baseline, 4 weeks of CMS program (for stressed and non-stressed rats, n = 12 for each group), and 1 week or 3 weeks after
the treatment of saline and escitalopram (10 mg/kg/d) (n = 6 for each subgroup). The CMS program was still ongoing during
the drug treatment stage. Values are presented as mean ± SEM; # or ## indicates P < 0.05 or 0.01 vs. baseline/saline condition;
** indicates P < 0.01 vs. non-stressed rats.
Non-stressed
Stressed
Non-stressed Rats
Stressed Rats
#
20
15
Corticosterone Concentration (ng/ml)
Sucrose Consumption (g)
140
*
10
5
0
CMS
CMS + Saline Injection
Fig. 4. Effects of CMS on sucrose consumption in younger rats
(n = 10 for each group). Rats received the same CMS
program and were evaluated by the sucrose consumption test after 1 week of saline injections. Values are presented as mean ± SEM; * indicates P < 0.05 vs. nonstressed rats.
were observed. However, the stressed rats still consumed a greater amount of sucrose when injected with
saline [t(10) = 1.9, P < 0.05] (Fig. 3, right panel).
A separate experiment with rats entering the
CMS program at 10 weeks old demonstrated that the
amount of sucrose consumption was significantly lower
in the stressed rats after 4 weeks [6.8 ± 1.2 vs. 11.7 ±
1.3, for stressed and non-stressed rats, respectively,
t(18) = 2.49, P < 0.05]. However, the 1-week saline
injection did not increase consumption for younger
rats [12.0 ± 1.5 vs. 13.7 ± 1.1, for stressed and non-
*
120
100
80
60
40
20
0
Saline
Escitalopram
Fig. 5. Effects of escitalopram on plasma corticosterone levels
in stressed and non-stressed rats. Samples were extracted
at the end of experiment when the rats were sacrificed
after the 8-week CMS program. Treatment of saline or
escitalopram (10 mg/kg/d) was carried out from Week 5
to Week 8 during the ongoing CMS program. Values are
presented as mean ± SEM; # indicates P < 0.05 vs. saline
condition; * indicates P < 0.05 vs. non-stressed rats.
stressed rats, respectively, t(18) = 0.36, not significant]
(Fig. 4).
For corticosterone concentration, a significant
effect of STRESS [F(1,21) = 6.94, P < 0.05] and
TREATMENT × STRESS [F(1,21) = 8.60, P < 0.01]
was observed. Further analysis revealed that simple
main effects existed for TREATMENT in the stressed
rats [F(1,21) = 9.78, P < 0.01] (Fig. 5).
6
Yang, Wang, Tung, Ko and Liu
Discussion
The present study demonstrated that adult SD rats
consumed less sucrose solution under CMS. However,
chronic escitalopram regime appeared not helpful in
reversing the CMS effect and, if any, the drug unexpectedly exaggerated the anxiety profile of the animals.
These findings are discussed below.
Consistent with a previous report (35), in the
present study escitalopram increased the travel distance in the locomotion test for all groups of rats.
This observation indicates that the change of locomotor activity is nonspecific (24), and a stimulant
effect of the drug, if exists, affects both the stressed
and the non-stressed rats. Sucrose consumption or
preference, however, is a more specific index of hedonic
level. Changes of this figure are useful for modeling
depression-like symptoms in terms of face validity,
and if the reduced sucrose consumption/preference
can be reserved by antidepressants, it is also useful
for predictive validity (20). The present study demonstrated that although CMS validated its role in anhedonia-like symptoms of depression, escitalopram
failed to reverse this CMS effect. For sucrose consumption, although bodyweight changes may not reflect the degree of depression (9), it may influence the
consumption result and should be taken into account.
We calculated the amount of consumed sucrose per
rat and per gram bodyweight, and both calculations
concluded that that the chronic regime of escitalopram appeared ineffective in treating CMS rats with
no hedonic deficit.
The underlying mechanisms of the above observations may be complicated; however, the following
factors should be considered. First, it was unlikely
that the rats disliked the taste, because the 2% sucrose
concentration used was far from the aversive range
due to over-sweetness, which is 7%-15% (26). Second,
the high level of sucrose consumption in the CMSSAL rats made it difficult for the therapeutic effect
of escitalopram to be prominent. Third, since rats
in our study were housed in groups, the CMS effects
were unlikely confounded by isolation-induced depression (11). This is particularly important for interpreting the effects of escitalopram, given that the
effects of SSRIs interact considerably with social isolation (4, 29).
On the other hand, our data seem to raise a possibility that individuals undergoing persistent stress might
develop an ability to cope with the depression, given
the evidence that the stress of repeated injections may
induce depression (19). In other words, persistent
stress itself may resemble the chronic antidepressant
treatment (7), which can be also interpreted as a stresscoping over-intake/consumption (13). This is plausible
because the phenomenon was more prominent after
one week rather than three weeks of injections, the
stress-coping consuming appeared degraded as the time
elapsed.
As mentioned in the Introduction, rat strain and
the protocol used can influence the outcome evaluation of CMS. This can be exemplified by a recent
work in which Papp and colleagues demonstrated
that citalopram, the original form of escitalopram,
reversed the CMS-decreased sucrose consumption
(27) by using the CMS-sensitive Wistar rat strain,
with a shorter CMS duration of two weeks before the
drug intervention, and a situation of singly housing
which may yield depression-like activities, to a degree
may have confounded the results (6, 10, 32, 39). In
the present study, CMS successfully reduced the sucrose
consumption in the SD rats, but the sensitivity was
not as well as the Wistar strain for contrasting effects
of the drug. Thus, Wu and Wang et al. (37) conclude
similarly that antidepressants are probably not helpful
for CMS-induced depression in SD rats. Our data are
clinically relevant because they may refer to a population of patients who are relatively insensitive to persistent and unpredictable stress (here, as the CMS program), and who may develop an anti-stress ability under
an add-on predicted stress (here, as repeated injections).
For these patients, antidepressant benefits may not be
as good as those stress-sensitive ones. The unexpected
effect of escitalopram is not a unique occurrence. In
fact, citalopram, the racemic form of escitalopram, has
been found to be ineffective in treating stressed-mice
with less hedonic deficit (33).
Aging may also influence the ability to cope with
stress. Herrera-Pérez et al. (16) reported that agedependent testosterone may play a role in stressinduced depression in which orchidectomized rats
of 3-5 months, corresponding to 18 week-old rats in
our experiments, did not increase their vulnerability
to develop anhedonia. The observation appeared to
justify the anti-stress ability of our adult rats. Note
that the rats entering the CMS program in the present
study were at their adult age, and were older than rats
at their preadolescent age reported in other CMS studies
(3, 30, 34, 39). To clarify whether the CMS effects obtained in our study were relevant to age, a separate experiment was performed using younger rats that entered the CMS program at their adolescent age (i.e.,
at 10 weeks old). The results revealed that these
younger rats developed less anti-anhedonia effects,
supporting our hypothesis that stress-induced effects
vary with age (5, 15).
Plasma cortisol levels in general represent the
function of the hypothalamic-pituitary-adrenal axis
and correlate with stress and depression (12, 25, 40).
A previously study demonstrated that SSRI antidepressants could reverse the CMS-increased plasma
level of corticosterone in rats if they were sensitive
Persistent Stress and Anti-Anhedonia
to the CMS program (38). Unexpectedly, our behavioral data showed that chronic escitalopram raised the
level of plasma corticosterone in CMS rats. Mechanisms leading to such observed increased corticosterone levels can be complex. It is noted that
citalopram, the original form of the drug, when
chronically administered renders a similar elevation
of the corticosterone levels in stressful SD rats (17).
Taken together, the present study demonstrated
that chronic escitalopram regime might not be helpful
in reversing the CMS-induced anhedonia-like symptoms and even unexpectedly exaggerate the anxiety
profile of the treated animals. We provide here a different perspective on stress-induced depression and
its interaction with antidepressants. However, some
limitations of the present study should be addressed.
First, we did not have the data showing the effects of
escitalopram in the young rats and, thus, there is a
lack of comparison versus the 18 week-old rats. Second,
a dosing pattern for escitalopram is necessary for future
studies to validate this paradoxical drug effects. Third,
a concomitant no-injection control group should be
included to validate injection-induced mood changes.
Finally, other features of depressive-like behavior, such
as increased floating in the forced swim test and decreased exploration of novelty are best included when
evaluating the stress-induced depression-like behaviors in rats.
Acknowledgments
The study was supported by the Taoyuan Armed
Forces General Hospital (grant number 10319), National
Defense Medical Center (grant number MAB102-83)
and Tri-Service General Hospital (grant number TSGHC104-128). Special thanks must go to Lundbeck, Denmark, for kindly providing the escitalopram.
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