Psychology, 2010, 1: 209-219
doi:10.4236/psych.2010.13028 Published Online August 2010 (http://www.SciRP.org/journal/psych)
209
Is a Divergent Central Serotonergic Activity
Responsible for Either Despair or Learning
Behavior in Intact Wistar or Sprague-Dawley CD
Rats, Respectively? A Concomitant Behavioral and
Electrochemical Analysis
Francesco Crespi
Biology Deparment, Neurosciences CEDD GlaxoSmithKline, Medicines Research Centre, Verona, Italy.
Received May 11th, 2010; revised June 28th, 2010; accepted June 30th, 2010.
ABSTRACT
Behavioral observations combined with electrochemical analysis have been performed in Wistar or Sprague-Dawley
CD rats in the attempt to clarify earlier controversial behavioral reports. In particular, these rats were submitted to
FST and to repeated Forced Swimming (rFS, during 4 days). In parallel, voltammetric in vivo analysis of serotonin
(5-HT) levels in platelet-rich plasma (PRP) collected daily from these animals was also performed as it is known that
peripheral 5-HT levels monitored in rat PRP mirror cerebral 5-HT contents. Thus, combined behavioral-voltammetric
studies allow deducing changes of central 5-HT levels that could be correlated to FST or rFS, with the advantage of
non invasive analysis of central neurotransmitter activities in intact behaving animals. In particular, combined behav-
ioral-voltammetric results suggest that “behavioral despair” is the process interesting Wistar rats when submitted to
FST or rFS while “learning to be immobile” is the process involving Sprague-Dawley CD rats.
Keywords: Rat Strains, Behavior, Electrochemistry, Fluoxetine, Serotonin, Platelets
1. Introduction
Many studies employing the forced swimming test (FST)
which is a behavioral test that predicts the clinical effi-
cacy of many types of antidepressant drugs [1] have been
done using Sprague-Dawley CD rats. A minor number of
such experiments have been done in Wistar rats. In the
Sprague-Dawley CD strain of rodents submitted to FST
in 15 cm water depth [2-5] or 30 cm water depth [6-10]
an antidepressant drug such as the selective serotonin
reuptake inhibitor (SSRI) fluoxetine produced dose-de-
pendent reduction of immobility at doses ranged between
5 or 80 mg/kg.
An antidepressant drug such as the selective serotonin
reuptake inhibitor (SSRI) fluoxetine at doses ranged be-
tween 5 or 80 mg/kg produced dose-dependent reduction
of immobility in Sprague-Dawley CD rats submitted to
FST performed in 15 cm water depth [2-5] or in 30 cm
water depth [6-10]. In contrast, treatment with fluoxetine
increased immobility in Wistar rats tested in deep water
(30 cm) [11,12] while a decrease or no modification of
immobility was monitored when FST was performed in
15 cm water depth [13,14]. Thus, following treatment
with fluoxetine, differences in immobility behavior be-
tween these two strains of rodents appear when tested in
lower water (15 cm) and become evident when tested in
deeper water (30 cm). Again, in Sprague-Dawley CD rats
peripheral fluoxetine (from 5 to 20 mg/kg) significantly
and dose-dependently increased swimming behavior [6,7,
11] while in Wistar rats only the highest dose of fluoxet-
ine did so [11]. Conversely, fluoxetine did not alter
climbing at any dose tested (5-80 mg/kg) in any of the
two rat species [4,6,8-11].
It is known that the swimming behavior is closely re-
lated to the activity of cerebral 5-HT [4,6]. Thus, one can
propose that the different sensitivity to fluoxetine behav-
iorally displayed by the two strains may be related to
dissimilarity within their serotonergic system.
The current study has been undertaken to analyse this
hypothesis. Sprague-Dawley and Wistar rats have been

Is a Divergent Central Serotonergic Activity Responsible for Either Despair or Learning Behavior in Intact 210
Wistar or Sprague-Dawley CD Rats, Respectively? A Concomitant Behavioral and Electrochemical Analysis
submitted to FST in deep water (30 cm) after intraperi-
toneal treatment with saline (vehicle) or with fluoxetine
20 mg/kg as this appears to be the dose significantly af-
fecting the swimming behavior within both types of ro-
dents [11]. Deep water has been selected as in such con-
ditions rats cannot support themselves by touching the
ground and they are obliged to swim and/or climb more
actively [4,6]. Furthermore, the duration of the swim-
ming test was prolonged up to a total of 4 days [15]. This
has been done since previous reports have observed de-
velopment of habituation in Wistar rats submitted to re-
peated FST [16-18] and that pharmacological blockade
of serotonergic activity enhances learning and memory
skills [19,20]. Those reports were followed by other
studies with the subsequent suggestion that the process
involved in FST could be “learning to be immobile”
[21,22] more than “behavioral despair” [1,3,4]. In the
present work, application of rFS to Sprague-Dawley and
Wistar rats together with electrochemical analysis of in
vivo serotonergic activities would investigate this hy-
pothesis. In particular, voltammetric measurements of
5-HT have been performed in PRP obtained from blood
collected from the tail vein of naive or “treated” con-
scious Sprague-Dawley or Wistar rats, daily.
Many clues in the literature suggest that “peripheral”
5-HT monitored in PRP is directly related to the levels of
cerebral 5-HT [23-27]. The feasibility of selective moni-
toring of 5-HT by means of voltammetry together with
specifically treated carbon fibre micro-electrodes (mCFE)
has been demonstrated either in brain as well as in blood
[28-32]. Furthermore, we have demonstrated that periph-
eral 5-HT levels monitored by means of differential pulse
voltammetry (DPV) together with mCFE in rat PRP
mirror cerebral 5-HT contents [28]. Therefore, in the
present work, this electrochemical methodology has been
applied to analyze daily the influence of behav-
ioral-pharmacological tests upon in vivo serotonergic
levels in the PRP of conscious rats. Substantially, moni-
toring “peripheral” 5-HT in PRP in alternative to the
analysis of cerebral 5-HT avoids submitting the rats to: 1)
Surgery performed under major reversible anesthesia i.e.
chloral hydrate [33,34] for implantation of the mCFE
within the brain; ii) Daily substitution of the exhausted
mCFE, performed under halotane anesthesia, when cen-
tral 5-HT is monitored chronically [35].
2. Material and Methods
2.1 Animals
Male Sprague-Dawley CD rats and male Wistar rats
(200-250g) were supplied by Charles-River (Italy) and
were kept in temperature- and humidity-controlled rooms
(22°C, 50%) with lights on from 0700 to 1900 hours with
water and food available ad libitum. All procedures were
carried out in accordance with the Italian law (Legisla-
tive Decree no.116, 27 January 1992), which acknowl-
edges the European Directive 86/609/EEC, and were
fully compliant with GlaxoSmithKline policy on the care
and use of laboratory animal and codes of practice. Fur-
thermore, all efforts were made to minimize the number
of animals used and their suffering.
2.2 Behaviour Studies
Rats were exposed to FST according to Porsolt et al. [1]
except that the water was deeper so that rats cannot mod-
ify the effects of the forced swim by developing behav-
ioral adaptations, such as when they touch the bottom or
sides of the tank. Briefly, the animals were placed indi-
vidually into a cylinder glass tank [40 cm height; 20 cm
diameter] containing water 30 cm deep and at 23-25°C
according to Detke et al. [6] and Detke & Lucki [4]. Two
swim sessions were conducted i.e. a 15-min pre-test fol-
lowed 24 h later by a 5-min test.
Separate groups of rats received intraperitoneally ei-
ther saline (Sprague-Dawley CD rats n = 5; Wistar rats n
= 5) or fluoxetine 20 mg/kg (Sprague-Dawley CD rats n
= 6; Wistar rats n = 6) in a volume of 2 ml/kg. Each
treatment was administered 23 h, 5 h and 1 h prior to the
test as described earlier [4,6]. The 20 mg/kg dose of
fluoxetine was also chosen because it has been demon-
strated that in some animal models of anxiety, acute
fluoxetine treatment may elicit a bell-shaped dose-re-
sponse curve with a maximum effect at 20 mg/kg [36].
Other 5 Sprague-Dawley rats and 5 Wistar rats were
exposed to a modified FST on four consecutive days.
The modified test was called rFS as described earlier
[15-17]. On the first day of rFS, rats swam for 15 min.
subsequently they were removed from the water tank and
dried under warm air. Other three swimming sessions of
5 min each were then conducted (spaced 24 h apart) on
the following three days.
A time-sampling method was used as described pre-
viously [6] in order to score several behaviors during a
single viewing. This method has been selected as it has
shown to be reliable and valid for detecting the effect of
different antidepressant drugs. In particular, immobility,
swimming and climbing was monitored in 5-sec period.
Briefly, immobility was scored when the animal was
making the minimum movements necessary to keep its
head above water and stay afloat. Swimming was scored
when the animal actively swam around the tank, making
movements greater than that necessary to stay afloat.
Climbing was scored when the animal made vigorous
thrashing movements with its forepaws in and out of wa-
ter. It was usually directed against the wall of the tank.
All the watching and scoring were performed by the

Is a Divergent Central Serotonergic Activity Responsible for Either Despair or Learning Behavior in Intact 211
W istar or Sprague-Dawley CD Rats, Respectively? A Concomitant Behavioral and Electrochemical Analysis
same observer within the behavior tests.
2.3 Voltammetric Studies
Immediately after each forced swimming session, each
rat was submitted to short (approximately 20 sec), light
halotane anesthesia so that blood can be collected from
tail vein (approximately 1ml/daily). The blood was cen-
trifuged 15 min at 200xg at room temperature to obtain
plasma rich-platelets (PRP) as described previously [37].
Successively, PRP was aspirated and re-suspended in
PBS pH 7.4. Then, mCFE coated with Nafion (Nafion-
mCFE) in order to selectively monitor serotonin [29,31,
38-41] were used in association with DPV to measure
5-HT content within PRP. More precisely, the mCFE and
the other two electrodes needed to apply DPV: the auxil-
iary and the reference electrode [30,42] were inserted in
200µl PRP obtained either from rats undergoing the be-
havioral test (rFS) or from naïve, control rats.
In order to verify the chemical nature of the DPV sig-
nal monitored in PRP as corresponding to the oxidation
of 5-HT, the following experiments have been per-
formed:
1) Addition of standard serotonin solution to PRP
preparation;
2) Incubation during 10 min at room temperature in
three KCl solutions (150 µM, 15 mM or 150 mM, re-
spectively).
3) Incubation during 10 min at room temperature in
three EGTA solutions (3, 10, or 30 mM, respectively).
2.4 Data Analyses
All data were averaged and were expressed in percent of:
1) The averaged control 5-HT basal levels in the volt-
ammetric analysis;
2) The averaged count of immobility behavior in vehi-
cle treated rats in the FST study;
3) The averaged count of different behaviors of day 1
in the rFS study, respectively. However, the statistics
were calculated from the raw data using repeated meas-
ures analysis of variance (two ways ANOVA) with
STATISTICA software version 6.0. In the case of statis-
tically significant differences between mean values pro-
duced by drug treatments versus controls (vehicle treat-
ment) main factor Dunnet post-hoc test was applied. Sta-
tistical significance was set at p < 0.05.
3. Results
3.1 Analysis of 5-HT Signal in PRP
The use of Nafion-mCFE has permitted the selective
analysis of 5-HT oxidation signal in PRP. This has been
at first demonstrated by the good linearity in current lev-
els monitored when progressive concentrations of ex-
ogenous serotonin were added to PRP. It was also sup-
ported by the absence of electrical response following the
addition of possible interfering substances that can oxi-
dize at the specific oxidation potential of 5-HT such as
uric acid and 5-OH-indoleacetic acid [43-45] (data not
shown). It appeared that basal levels of 5-HT in the PRP
of Wistar and Sprague-Dawley CD rats were similar:
approximately 0.27 ± 0.05nA and 0.22 ± 0.06nA, respec-
tively. In addition, in both strains, the 5-HT signal moni-
tored in PRP was progressively increased in the three
KCl solutions, whilst it was reduced in a dose-dependent
manner until disappearance in the three EGTA solutions
(see Figure 1).
3.2 FST and Fluoxetine
When submitted to modified FST, significantly larger
counts of immobility were monitored in the pre-test day
and test day for Wistar rats versus Sprague-Dawley rats,
i.e. 37.5 and 47.0 counts versus 25.3 and 38.7 counts,
respectively.
Figure 1. DPV analysis of 5-HT levels monitored with
Nafion-mCFE in PRP incubated in KCl (TOP, n = 4 sam-
ples each concentration) or in EGTA (BOTTOM, n = 4
samples each concentration) during 10 min at room tem-
perature. Data are expressed as percent of control values
obtained in PRP maintained in PBS during 10 min at room
temperature. (n = 4 samples). Mean ± sem, * p < 0.05

Is a Divergent Central Serotonergic Activity Responsible for Either Despair or Learning Behavior in Intact 212
Wistar or Sprague-Dawley CD Rats, Respectively? A Concomitant Behavioral and Electrochemical Analysis
Furthermore, in male Wistar rats pre-treated with
fluoxetine (20 mg/kg i.p.), behavioral observations indi-
cated a significant increase of immobility up to 156.3%
of control when submitted to FST in deeper water (30
cm). In contrast, male Sprague-Dawley CD rats treated
with fluoxetine (20 mg/kg i.p.) and then submitted to
FST did show a significant decrease of the immobility
behavior to 79.4% of control (Figure 2). The two ways
ANOVA test revealed significant effect of strain and
treatment versus strain interaction (see Table 1).
0
20
40
60
80
100
120
140
160
180
Wistar rats SD rats
mean count of im mobili ty
% of vehicle t reated group
v ehicle fluoxetine
*
*
Figure 2. Effect of acute treatment with fluoxetine (■ 20 mg/kg
i.p.) on immobility behavior in Wistar rats or Sprague-
Dawley CD (SD) rats (n = 6 each strain) submitted to FST.
Data are expressed as % of control values obtained in vehi-
cle treated rats (□ saline, 2 ml/kg i.p., n = 5). Mean ± sem, *
p < 0.05
Table 1. Results of the two ways ANOVA test
Factor F-value p-value
FST & Fluoxetine
Immobility Treatment 1.02 0.32
Strain 5.40 0.033
Treatment vs. strain 18.8 0.0004
rFS
Immobility Treatment 9.83 0.0001
Strain 26.5 0.0001
Treatment vs. strain 0.11 0.95
Climbing Treatment 2.41 0.085
Strain 31.5 0.0001
Treatment vs. strain 1.91 0.15
Swimming Treatment 15.24 0.0001
Strain 9.46 0.0043
Treatment vs. strain 1.11 0.36
Voltammetry after
rFS
5-HT levels in PRP Treatment 15.38 0.0001
Strain 7.06 0.012
Treatment vs. strain 3.62 0.024
3.3 rFS
rFS has been performed during four days, including the
first day pre-test. The counts of the three types of behav-
ior analyzed (immobility, climbing, swimming) were
taken in the first 5 min of the pre-test day and in the 5
min test of the successive three days. They revealed a
similar trend of immobility in the two strains of rats; in
particular Wistar rats displayed significantly (p < 0.05)
greater rate of immobility than Sprague-Dawley CD rats:
approx. 46.8 counts versus 38.2 counts, respectively
(Figure 3). On the other hand, the two active behaviors
climbing and swimming displayed different patterns in
the two species of rats:
1) In Wistar rats, a significant decrease (p < 0.05) of
the counts of climbing behavior was observed on the
second day only; in the third and the fourth day the
counts were similar to those of first day (Figure 3);
2) In Sprague-Dawley rats climbing behavior de-
creased significantly the third and fourth day (17.6
counts) versus the first day (26.2 counts) (Figure 3 ).
Wistar rats
0
10
20
30
40
50
60
Immobility Climbing Swimming
Mean count of imm obility,climbin
g
or swimm ing
DAY1
DAY2
DAY3
DAY4
**
*
**
*
*
SD rats
0
10
20
30
40
50
60
Immobility Climbing Swimming
Me a n c o u n t o f immo b ility ,c limb in
g
o r s w immin g
DAY1
DAY2
DAY3
DAY4
*
*
*
*
*
*
Figure 3. Counts of immobility, climbing and swimming
behaviors sampled every 5 sec during the first 5 min of
pre-test day (day 1) and during the 5 min of the rFS (days
2-4) estimated in Wistar rats (TOP) or Sprague-Dawley CD
(SD) rats (BOTTOM) (n = 5 each strain). Mean ± sem, * p <
0.05

Is a Divergent Central Serotonergic Activity Responsible for Either Despair or Learning Behavior in Intact 213
W istar or Sprague-Dawley CD Rats, Respectively? A Concomitant Behavioral and Electrochemical Analysis
Data obtained evaluating swimming in Wistar rats
showed a rapid significant decrease of this behavior that
was virtually disappeared during the third and fourth day
of rFS. In Sprague-Dawley rats swimming behavior pre-
sented a significant decrease at the second day versus the
first day, but at the third and fourth day of rFS the
swimming behavior returned to values not significantly
different from those of the first day (Figure 3). The re-
sults of the two ways ANOVA test revealed significant
main effects of treatment and strain in all behaviors apart
from climbing where p value for treatment was 0.08
(Table 1).
3.4 Voltammetry after rFS
In both strains, 5-HT levels were electrochemically
monitored within 200 µl of PRP, daily.
The voltammetric results obtained in Wistar rats
showed the 5-HT levels monitored in PRP decreased
progressively; the third day of rFS they were signifi-
cantly reduced to 71% of control values recorded in PRP
of naïve rats. In contrast, in Sprague-Dawley rats,
PRP-5-HT levels showed a significant increase at the
first day of rFS while returning to values similar to those
of control naïve rats the second and third day of the ex-
periment (Figure 4). The results of the two ways
ANOVA test revealed significant main effects of strain,
treatment and strain by treatment interaction (see Table
1). In addition, significant correlation between swimming
scores and 5-HT levels in PRP of the Wistar rats only has
been determined: r = 0.53, p = 0.015.
4. Discussion
FST is described in the literature as a “behavioral de-
spair” test [1,3,4] as it produces a change in behavior i.e.
an immobile posture that is considered “a key symptom
of the depressive state, namely that of despair or help-
lessness” [3]. On the other hand it has been also sug-
gested that the resulting behavior following FST could be
due to the possibility that “the subject learns to be immo-
bile in the first session”, being the second one a “retention
test” (learned immobility hypothesis) [18,21,22]. Fur-
thermore, it is described that Wistar rats display less mo-
bility than Sprague-Dawley CD rats when submitted to
FST [11]. From these data one could hypothesize either
that:
1) Wistar rats are more sensitive to stress than Spra-
gue-Dawley CD rats and so their greater immobility
could be correlated to a “behavioral despair”;
or that:
2) Wistar rats display a greater memory and learning
skills than Sprague-Dawley CD rats.
Therefore, in this study the hypothesis that the process
involved in the FST could be “learning to be immobile”
more than “behavioral despair” has been investigated in
Wistar rats and in Sprague-Dawley CD rats. Putative
differences in behavior during FST or rFS (4 days) and
the effect(s) of fluoxetine (SSRI) upon responses to FST
were analyzed in these two strains.
At first we have confirmed data from the literature
showing larger counts of immobility in Wistar rats versus
Sprague-Dawley CD rats when submitted to FST (see
Figure 3). Successively, a modified version of FST, so
called rFS [15-17] has been applied so that putative dif-
ferences in behavioral responses between Sprague-Daw-
ley CD rats and Wistar rats could be evaluated.
Data show a significant increase of immobility in both
strains within the second day of the rFS test and continu-
ing the third and the fourth day of rFS in both types of
rats (see Figure 3). Because of the numerous factors in-
fluencing the FST test, it has been suggested that the time
Wistar rats
0
20
40
60
80
100
120
140
160
DAY 1DAY 2 DAY 3DAY 4
5- HT % of control
rFS
*
SD rats
0
20
40
60
80
100
120
140
160
DAY 1DAY 2DAY 3DAY 4
5-HT % of co ntrol
rFS
*
Figure 4. Influence of rFS upon DPVoltammetric 5-HT
levels monitored in PRP prepared from blood collected
daily at the end of each FS session from tail vein of Wistar
(n = 5) or Sprague-Dawley CD (n = 5) rats. Data are ex-
pressed as percent of control values obtained by measuring
5-HT levels in PRP prepared from blood of five naïve rats.
Mean ± sem, * p < 0.05

Is a Divergent Central Serotonergic Activity Responsible for Either Despair or Learning Behavior in Intact 214
Wistar or Sprague-Dawley CD Rats, Respectively? A Concomitant Behavioral and Electrochemical Analysis
of immobility on the second day of rFS might be consid-
ered a nonspecific parameter referred to as “learning to
be immobile” rather than “behavioral despair” [21]. The
present data also show that treatment with fluoxetine
actually increases immobility as well. Since fluoxetine is
a compound that inhibits serotonin reuptake, thus making
it more available at its receptors, this result could appears
like a contradiction, however in the Porsolt’ test the
SSRIs have been found to be ineffective or even pro-
longing the time of immobility [6,46]. Similarly, while in
the literature, the results concerning the ineffectiveness
of the SSRIs in rats are still controversial, it has been
constantly reported that the SSRIs extend the time of
immobility in mice [46]. It is also well known that acute
treatment with SSRIs may produce anxiogenic-like ef-
fects in humans [47] as well as in animals [48]. Further-
more, Borsini et al. [49] have indirectly illustrated that
the emotional state of an animal might be important for
the outcome of the test. Accordingly, our data show that
Wistar rats display greater immobility and that is in
agreement to the reported observation that such an inbred
rat strain is inclined to higher behavioral and physiologi-
cal responses to stress across a variety of situations in
comparison to other strains [15]. This would also explain
the significant decrease of swimming mainly observable
in Wistar rats.
4.1 Voltammetry in PRP
Concomitant in vivo DPVoltammetric analysis per-
formed accordingly with Zen et al. [32] has shown that
the signal monitored with Nafion-mCFE in PRP at the
oxidation potential of 5-HT was selectively sensitive to
addition of exogenous 5-HT (data not shown). Further-
more, experiments performed in PRP accordingly with
Barja-Fidalgo et al. [50] have shown that incubation in
KCl stimulates increase of the 5-HT related DPV signal.
Finally, accordingly with Lyons and Shaw [51] treatment
of PRP with the calcium-chelating agent EGTA has
demonstrated a dose dependent reduction of the 5-HT
related signal (see Figure 1). Thus, these DPVoltammet-
ric data support the chemical nature of the signal moni-
tored in PRP as corresponding to the oxidation of basal,
endogenous 5-HT level in PRP. Successively, DPV
measurements performed during the behavioral tests
showed that 5-HT level in PRP decreased progressively
in Wistar rats submitted to rFS, while they increased at
day 1 of rFS in Sprague-Dawley rats and returned to
control levels the next days. The fact that “peripheral”
5-HT levels [in PRP] mirror central 5-HT levels has been
already documented [23-27]. Therefore the present data
on 5-HT level in PRP of Wistar rats taken together with
the observation that pharmacological blockade of sero-
tonergic activity enhance learning and memory skills
[19,20] may suggest that the increased immobility fol-
lowing rFS monitored in Wistar rats could be due to
“learning to be immobile” more than “behavioral de-
spair”. Thus, the concomitant decrease of 5-HT levels
monitored in PRP and considered as peripheral marker of
modifications of central 5-HT system may be correlated
to the enhancement of learning skill; i.e. it could lead
Wistar rats to develop habituation to be immobile when
submitted to rFS. Conversely, other authors have re-
ported that serotonin receptor agonists deteriorate such
skills [52,53], therefore the hypothesis proposed above is
still matter of discussion. When related to the same ob-
servation reported above [19,20] the significant increase
of 5-HT level in PRP of Sprague-Dawley CD rats leads
one to consider that in this strain of rats the significant
increase of immobility following rFS could be unrelated
to “learning to be immobile” but may be interpreted in
the light of a “behavioral despair” hypothesis. However,
this conclusion is in disaccord with the finding that (diet)
tryptophan restriction, and therefore brain serotonin re-
duction, could impair normal cholinergic activity in some
brain areas such as the hippocampus and the cerebral
cortex that are involved in learning and memory proc-
esses [54]. These observations lead to the comment that
work remains to be done to further elucidate the con-
trasting data present in literature on this matter. De-
creased levels of central 5-HT has been recently reported
in Wistar rats submitted to rFS [55]. Our voltammetric
data on 5-HT levels monitored in PRP of Wistar rats
match these recent findings which therefore support the
proposal that peripheral 5-HT levels monitored by means
of DPV together with mCFE in rat PRP mirror cerebral
5-HT contents.
Furthermore and on the basis of the 5-HT hypothesis
of depression suggesting a relationship between vulner-
ability to this illness and a deficit in the brain serotoner-
gic activity [56] the depletion of 5-HT caused by forced
swimming may be one of the reasons for the develop-
ment of depressive-like behavior in Wistar rats.
On the other hand, the observation of an increased
level of 5-HT on day 2 returning to ‘control” values on
days 3 and 4 in the PRP of Sprague-Dawley CD rats lead
one to propose that there is not such a central 5-HT defi-
cit in this second strain of rats. This is supporting the
idea that rFS may display learning behavior in Spra-
gue-Dawley CD rats as the present results suggest that
experience and learning may be the principal processes at
the basis of the significant increase of immobility in
Sprague-Dawley CD. Indeed, in these rats, immobility
levels were continuously increasing during the 3 days of
rSF following the pre-test day (day 1, see Figure 3),
without reaching a plateau while showing higher vari-
ability on their response when compared to that of Wistar
rats (see Figure 3). In contrast, the Wistar rats submitted
to rFS present less mobility than the Sprague-Dawley CD

Is a Divergent Central Serotonergic Activity Responsible for Either Despair or Learning Behavior in Intact 215
W istar or Sprague-Dawley CD Rats, Respectively? A Concomitant Behavioral and Electrochemical Analysis
rats; i.e. they show less variability on their response (see
Figure 3 top) and reach a stable (plateau) level of immo-
bility the third and fourth day of the test. Thus, “behav-
ioral despair” seems to be the cause of the increased im-
mobility in Wistar rats as their “answer” to the recurring
stress produced by the repetition of the test is the ‘sud-
den’ increased immobility to a plateau as indeed found at
the third and fourth day of rFS. Accordingly with previ-
ous studies indicating that various stressors alter 5-HT
synthesis / turnover [57,58], the different behavior within
these two strains may therefore also be related to the dif-
ferent biochemical “reaction” of their 5-HT central sys-
tem when submitted to FST: i.e. progressive decrease of
5-HT levels in Wistar rats versus a significant increase in
day 1 followed by return to control values days 2 and 3
in Sprague-Dawley CD rats (Figure 4).
The present study also shows a rapid decrease of
swimming until virtually its disappearance during the
third-fourth day of rFS in Wistar rats. In contrast, in
Sprague-Dawley rats swimming behavior presented a
significant decrease at the second day versus the first
testing day, but at the third and fourth day it returned to
values not significantly different from those recorded in
the first day of rFS. Again, this difference in swimming
behavior between the two strains of rats could be related
to the difference in 5-HT levels monitored after each
swimming session in PRP of both species of rats. In
Wistar rats 5-HT levels monitored in PRP decreased
progressively; reaching the minimum significant value at
the third day of rFS. In Sprague-Dawley rats, 5-HT levels
in PRP showed a significant increase at the first day of
rFS, returning to values similar to those of control rats
the following days of experiment. This is in accord with
the relationship described in literature between seroton-
ergic system activities and swimming behavior during
FST: in particular an enhancement of 5-HT neurotrans-
mission mediates positively the swimming behavior of
Sprague-Dawley CD rats [4,6].
Moreover, it is interesting to note the different climb-
ing behavior displayed by the two rat strains when sub-
mitted to rFS:
1) Progressive decrease of climbing in Sprague-Daw-
ley CD rats;
2) Initial decrease followed by a return to the values of
day 1 in Wistar rats.
Therefore, when submitted to rFS, these two strains of
rats display opposite swimming and climbing behaviors
(see Figure 3). Briefly:
1) In Wistar rats climbing at first decreased [day 2]
then restored the levels of day1 while swimming de-
creased progressively;
2) In Sprague-Dawley CD rats climbing decreased
progressively while swimming at first decreased [day 2]
then tended to return to the initial levels.
It is reported that climbing is a behavior mediated by
noradrenergic neurotransmission and swimming a be-
havior mediated by serotonergic neurotransmission [4,6].
Thus, one can argue that the behavioral data monitored
here, could be an index of distinct activities of the two
neurotransmitter systems within the two strains of rats
when submitted to FST as well as to rFS. In particular,
the dissimilarity observed within the serotonergic system
of the two strains i.e. when submitted to rFS may account
for the different behavioral response to fluoxetine treat-
ment observed here i.e. either increase or reduction of
immobility in Wistar rats or in Sprague-Dawley CD rats,
respectively (see Figure 2). Accordingly, the data con-
cerning swimming counts led one to argue about the ad-
ditional presence of a divergent activity of the noradren-
ergic system in the two rat strains during FST or rFS.
Further studies should be done to analyze this point. Yet,
it is interesting to note the parallel, significantly related
decrease of swimming counts and 5-HT levels monitored
in PRP of the Wistar rats submitted to rFS (see Figure 5).
Taken together with the findings that reductions of
noradrenaline or 5-HT, which do not by themselves im-
pair place learning, aggravate the place-learning deficit
produced by reductions of Ach [59] the present data
support the idea that in Wistar rats the increased immo-
bility following rFS could be due to “behavioral despair”
more than “learning to be immobile”. On the contrary,
the lack of change on 5-HT levels as well as in swim-
ming behavior observed in the Sprague-Dawley CD rats
may suggest that the increased immobility following rFS
could be due to “learning to be immobile” more than
“behavioral despair”.
Differential sensitivity to the behavioral effects of
fluoxetine by different rat strains has been already re-
ported. In particular it has been shown that genetic or
constitutive differences may determine the distinct be-
havioral profiles for antidepressant compounds with se-
lective pharmacological effects in different rat strains
such as male Sprague Dawley and Wistar Kyoto rats [11,
60]. The latter is a line derived from Wistar rats, pre-
senting significant higher plasma levels of corticosterone
and ACTH compared to Wistar rats that are the “control
line” of the Wistar Kyoto rats [61]. On the other hand,
these authors have also shown that Wistar rats exhibited
significantly longer immobility duration in the swim test
compared with the Sprague-Dawley CD rats. This is in
accord with the present observation of a significantly
higher counts of immobility in Wistar rats versus Spra-
gue-Dawley CD rats submitted to rFS (see Figure 3 and
Table 1). Altogether such results suggest that different
rat strains may demonstrate great variability in the be-
havioral response to antidepressants according to their
genetic or constitutive differences as well as pharmacol-
ogical selectivity, differences that should be not ruled out

Is a Divergent Central Serotonergic Activity Responsible for Either Despair or Learning Behavior in Intact 216
Wistar or Sprague-Dawley CD Rats, Respectively? A Concomitant Behavioral and Electrochemical Analysis
WISTAR rats
0
1
2
3
4
5
6
7
8
DAY 1DAY 2DAY 3DAY 4
5- HT [nA x10]
swimm in g co unts
SD rats
0
1
2
3
4
5
6
7
8
9
DAY 1DAY 2DAY 3DAY 4
5- HT [ nA x10]
swim m ing counts
Figure 5. Influence of rFS upon swimming and DPVoltam-
metric 5-HT levels monitored in PRP prepared from blood
collected daily at the end of each FS from tail vein of Wistar
rats (n = 5) or Sprague-Dawley CD rats (n = 5). Mean
counts (± sem) are shown together with 5-HT levels (i.e.
nanoAmperes [nA] multiplied by 10 for graphic purpose).
Significant correlation between swimming scores and 5-HT
levels in PRP of Wistar rats has been determined: r = 0.53,
p = 0.015
when evaluating behavioral and neurochemical changes
in response to antidepressants such as fluoxetine. In this
sense, it is worth mentioning that it has recently been
shown that four 5-HT receptor systems (5-HT1A, 5-HT2A,
5-HT4, 5-HT6) are highlighted as suitable targets for en-
hancing cognition and memory (for a review see [62])
with in particular the 5-HT6 receptor playing a role in
learning and memory processes in healthy and disease
states (see reviews by Mitchell and Neumaier [63] and
Schreiber et al. [64]). The putative synergistic interaction
of 5-HT6 receptors with other serotonin receptors is also
shown to be important for memory processes [65].
Therefore, differences in such aspects within the differ-
ent strains of rats may also account for the variability in
behavioral responses.
5. Conclusions
In conclusion, the present in vivo electrochemical analy-
sis support our previous work showing that peripheral
5-HT levels selectively monitored in rat PRP by means
of DPV together with Nafion-mCFE mirror cerebral
5-HT contents [28]. In particular it allows deducing
changes of central 5-HT levels that could be correlated to
behavioral tests such as FST or rFS. Therefore, this in
vivo approach displays the clear advantage of non inva-
sive behavioral-pharmacological analysis of neurotrans-
mitter activities in conscious animals. Finally, while fur-
ther work is needed to support the following idea, the
combined behavioral-pharmacological data presented
suggest that “learning to be immobile” seems to be the
process involved in Sprague-Dawley CD rats submitted
to rFS while “behavioral despair” seems to be the process
involved in Wistar rats submitted to rFS.
6. Acknowledgements
For technical support to Dr. E. Vecchiato and Dr. C.
Lazzarini.
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