Vol. 34, No. 10, pp. 1305-1310, 1995
Copyright 0 1995 Elsevier Science Ltd
Printed in Great Britain. All rights reserved
0028-3908/95 $9.50 + 0.00
The Effect of 5-HTIA Receptor Ligands in a
Mild Stress Model of Depression
E. PRZEGALIfiSKI*, E. MORYL and M. PAPP
Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St, 31-343 Krakow, Poland
(Accepted 9 June 1995)
stress model of depression.
of time show a subsrantial
sensitive to repeated treatment
deficit in the sucrose intake was gradually reversed by chronic (3-5 weeks) administration
5 mg/kg, Lp., b.i.d.) or WAY 100135 (10 mg/kg, s.c., b.i.d.), but not 8-OH-DPAT
ipsapirone (5 mg/kg i.p., b.i.d.). The magnitude
to that observed following similar administration
citalopram (10 mg/kg i.p.). Increases in the sucrose
WAY 100135, imipramine and citalopram
non-stressed animal:3 was unchanged by any drug. These results suggest that buspirone
have antidepressant properties. Possible links between
interaction with 5-HTIA receptors and/or the dopamine
properties of S-HTIA receptor
and the selective antagonist
In this model, rats subjected
decrease in the consumption
ligands (the full agonist &OH-DPAT,
WAY 100135) were studied in a chronic mild
to a variety of mild stressors
of a 1% sucrose solution (anhedonia),
drugs. In the present study we found that the stress-induced
for a prolonged period
an effect being
(0.5 mg/kg, s.c., b.i.d.) or
and WAY 100135 was comparable
animals; the behaviour
and WAY 100135 may
the anti-anhedonic effect of these drugs and their
system are discussed.
of the effect of buspirone
of the antidepressant
were specific to the stressed
(10 mg/kg i.p.) or
animal model, anhedonia,
WAY 100135, rat.
Several data indicate an. association
serotonin (5-HT) and the pathogenesis of depression (see
Coppen and Doogan, 1988; Lopez-Ibor,
et al., 1991). Among otheris, over the last decade a grow-
ing body of evidence has suggested that 5-HT,, receptor
ligands may represent a new class of mixed anxiolytic/
antidepressant drugs. In fact, the 5-HT,, receptor partial
agonists buspirone, ipsapirone and gepirone, have been
reported to be anti-anxiety drugs in both preclinical and
clinical studies (see Traber and Glaser, 1987; Schreiber
and de Vry, 1993; Eison and Eison, 1994; Pecknold, 1994).
Similarly, those drugs were also found to be active in some
animal models of depression and in depressed patients
(see Schreiber and de Vry, 1993; Lucki et al., 1994;
Pecknold, 1994). Moreovl:r, an antidepressant
has recently been suggeisted for 5-HTIA antagonists
(Fletcher et al., 1993a). Interestingly, some evidence also
indicate a role of 5-HTIA receptors in the mechanism of
action of several antidepressant
cyclics, monoamine oxidase inhibitors and selective 5-HT
uptake inhibitors (see: Newman et al., 1993; Stahl, 1994).
drugs, including tri-
*To whom correspondence should be addressed.
imipramine, citalopram, &OH-DPAT, ipsapirone,
Recently a new animal model of depression has been
developed by Willner and his colleagues. In this model,
rats subjected to a variety of mild stressors for a prolonged
period of time show a substantial decrease in their
responsiveness to rewarding stimuli; such a deficit is
usually demonstrated as a decrease in the consumption of
a palatable 1% sucrose solution (Willner et al., 1992).
Since the subsensitivity to reward appears to reflect
anhedonia, which is a core symptom of depression, a
chronic mild stress (CMS) procedure may serve as a
suitable experimental model to study antidepressant
A series of previous
CMS-induced anhedonia can be effectively reversed by
chronic treatment with antidepressant
tricyclics, atypical antidepressants
oxidase inhibitors, but not with drugs devoid of an
antidepressant activity (Willner et al., 1992; Papp et al.,
1995). In the present paper the CMS model was used to
study the antidepressant properties of 5-HTIA receptor
ligands. We searched for anti-anhedonic
5-HT,, receptor full agonist 8-hydroxy-2-(di-n-propy-
1amino)tetralin (8-OH-DPAT) (Middlemiss and Fozard,
studies showed that the
effects of the
E. Przegalinski et al.
1983) the 5-HT,, receptor partial agonists buspirone and
ipsapirone (Fozard, 1987) and the 5-HTIA receptor
selective antagonist N-tert-butyl-3/4-(2_methoxyphenyl)-
Imipramine and the selective 5-HT uptake inhibitor
citalopram (Hyttel, 1994) were used as reference drugs.
Male Wistar rats (obtained from a licensed dealer) were
brought to the laboratory
experiment was started. Except as described below (see
stress procedure), the animals were singly housed in
plastic cages (40 x 25 x 15 cm), with food and water
freely available, and were maintained
light/dark cycle at a temperature of 22 f 2 “C. At the
start of the experiment the animals weighed 30&350 g.
two months before the
on a 12 hr
All animals were first trained to consume a sucrose
solution. The training consisted of seven 1 hr baseline
tests, in which 1% sucrose solution was presented, in the
home cage, following 14h of food and water deprivation.
The intake was measured by weighing pre-weighed bottles
containing the sucrose solution at the end of the test.
Subsequently, the sucrose consumption was monitored
under similar conditions, at weekly intervals, throughout
the whole experiment. On the basis of their sucrose
intakes in the final baseline test, the animals were divided
into two matched groups. One group of animals was
subjected to a chronic mild stress procedure for a period
of 9 weeks. Each week of the stress regime consisted of:
two periods of food or water deprivation, two periods of
45” cage tilt, two periods of intermittent
illumination (light on and off every 2 hr), two periods of
soiled cage (200 ml water in sawdust bedding), two
periods of paired housing, two periods of low intensity
stroboscopic illumination (150 flashes/min).
stressors were of a 12-14 hr duration and were applied
continuously, day and night. Non-stressed
animals were housed in a separate room and had no
contact with the stressed animals. They had food and
water freely available in their home cage, except for a
14 hr period of food and water deprivation, preceding
each sucrose test.
The study consisted of 2 consecutive experiments. In
each experiment, on the basis of sucrose intake scores
following 3 weeks of stress, both stressed and control
animals were further divided into matched subgroups.
Subsequently, separate groups of control and stressed
animals (n = 8 rats/group)
vehicle, imipramine (10 mg/kg,
(0.5 mg/kg, s.c., b.i.d), ipsapirone (5 mg/kg i.p., b.i.d.)
and buspirone (2.5 mg/kg i.p., b.i.d) for six weeks
(Experiment 1). In Experiment 2, vehicle, imipramine
(10 mg/kg, i.p.), citalopram (10 mg/kg, i.p.), buspirone
(5 mg/kg i.p., b.i.d), and WAY 100135 (10 mg/kg s.c.,
b.i.d) were administered for 5 weeks. In both experiments
stress was continued throughout the treatment period,
and weekly sucrose tests were carried out 22 hr after the
last drug administration.
The following agents were used: imipramine (Polfa),
citalopram (Lundbeck), 8-OH-DPAT (RBI), ipsapirone
(Troponwerke), buspirone (RBI) and (S)-WAY 100135
(synthesized by Dr J. Boksa, Institute of Pharmacology,
Krakow). All agents were dissolved in distilled water
which was used for the vehicle administrations.
The results were analyzed by a multiple analysis of
variance, followed by the Fisher’s Least Significant
Difference (LSD) test for post hoc comparisons when
In all the experiments chronic mild stress caused a
decrease in the consumption of a 1% sucrose solution,
Table 1. The effect of chronic treatment with vehicle, imipramine, I-OH-DPAT, ipsapirone or buspirone
on the sucrose intake (g) in control and stressed animals
Imipramine (10 mg/kg, i.p.)
I-OH-DPAT (0.5 mg/kg, s.c., b.i.d.)
Ipsapirone (5 mg/kg, i.p., b.i.d.)
Buspirone (2.5 mg/kg, i.p, b.i.d.)
Week 0 Week 1
13.3 + 0.5
7.6 + 0.8***
13.4 + 0.4
7.8 + 0.6***
13.4 f 0.4
7.7 + 0.6***
13.2 7 0.5
7.7 If: o.s**
13.3 f 0.4
7.7 + 0.5***
12.9 f 0.5
6.7 f 0.4***
12.1 f 0.5
9.4 f 0.7**
13.9 * 0.9
8.3 f 0.7***
12.3 f 0.4
9.2 + 1.1;
12.6 + 0.4
6.9 + l.l***
11.6 f 1.2
7.9 f 0.4**
12.1 * 1.2
13.1 + 1.3##
12.8 z 2.9
8.7 f 0.9;
10.4 f 1.7
8.8 * 0.9*
11.9 f 1.3
13.8 + l.l###
The data are means (+ SEM) of the sucrose intake in control and stressed animals after 0, 1 and 6 weeks
*P < 0.05, **P < 0.01, ***P < 0.001; relative to controls.
relative to Week 0.
##P < 0.01, ###P < 0.001;
5-HTIA receptor ligands in an animal model of depression
1 2 3
Weeks of treatment
Fig. 1. The effect of chronic treatment with vehicle (Veh),
imipramine (IMI, 10 mg/kg) or citalopram (CIT, 10 mg/kg) on
the consumption of a 1% sucrose solution in controls (Con,
open symbols) and animals exposed to chronic mild stress (Str,
closed symbols). Treatment commenced after 3 weeks of stress.
The values are means; stand.ard errors have been omitted for
clarity. All drug-treated stressed animals differ significantly (at
least P < 0.05) from baseline (Week 0) after 2, 3,4 and 5 weeks
of treatment. *P < 0.05, **P < 0.01; relative to vehicle-treated
(exp. 1: P < 0.001, Table 1; exp. 2: P < 0.01, Figs. 1 and
2). In all animals treated with vehicle, such a difference
persisted at a similar level for the remainder
treatment period [exp. 1: 1c(1,42) = 82.9, P < 0.001; exp.
2: F(1,84) = 36.45, P < O.OOl]. None of the drugs tested
in this study had any significant
consumption in control animals
NS; exp. 2: F(20,210) = 0.55, NS]. In stressed animals,
however, imipramine and citalopram
in the sucrose intake, which
the start of treatment,
and stressed animals were significantly
effect on the sucrose
[exp.l: F(8,105) = 0.24,
caused an increase
resulted in a significant
Weeks of treatment
Fig. 2. The effect of chronic treatment with vehicle (Veh),
buspirone (Bus, 5 mg/kg b.i.d.) or WAY 100135 (WAY,
10 mg/kg b.i.d.) on the consumption
in controls (Con, open symbols) and animals exposed to chronic
mild stress (Str, closed symbols). Treatment commenced after 3
weeks of stress. The values are means; standard errors have been
omitted for clarity. All drug-treated
significantly (at least P < 0.05) from baseline (Week 0) after 4
and 5 weeks of treatment.
*‘P < 0.05, **P < 0.01; relative to
of a 1% sucrose solution
stressed animals differ
ment x Weeksinteraction
F(5,84) = 2.68, P < 0.02, respectively].
of the action of imipramine
Fig. 1. The sucrose intake in stressed animals treated with
those drugs improved significantly
treatment; this effect was maintained
5 weeks of treatment the sucrose intake
between drug-treated stressed animals and vehicle-treated
controls (Fig. 1).
The stress-induced decrease in the sucrose intake was
also reversed by buspirone administered
of 2.5 mg/kg for 6 weeks [F(1,42)=
at a dose of 5 mg/kg for 5 weeks
P < O.OOl]. The time-course
shown in Fig. 2. The drug appears to act more slowly than
imipramine and citalopram
the sucrose intakes was seen before 4 weeks of treatment.
However, at the end of the treatment
significant differences between the drug-treated
animals and the vehicle-treated
(Table 1 and Fig. 2). A similar recovery
induced decrease in the sucrose intake was observed
animals treated with WAY
P < O.OOl]. As illustrated in Fig. 2, this treatment
showed a slower onset of action, and the full effect was
apparent after 4 weeks of treatment.
An analysis of the data obtained
drugs revealed that there were no significant
ences between any treatments
F(3,336) = 1.75,
0.59, Treatment x Groups x Weeks: F(15,336) = 0.661,
suggesting that the long-term
citalopram, buspirone and WAY 100135 causes compar-
able therapeutic effects on the stress-induced
the consumption of the sucrose solution.
Table 1 shows that, in contrast
8-OH-DPAT and ipsapirone
stress-induced deficit in
[treatment effect: F( 1,42) = 1.54, NS; and F( 1,42) = 0.48,
NS, respectively]. Following
the sucrose intake in stressed
significantly lower than in the vehicle-treated
[8-OH-DPAT: F(1,42) = 21.79, P < 0.001; ipsapirone:
F(1,42) = 19.24, P < O.OOl].
F( 1,84) = 18.40, P < O.OOl], and
[F(5,84) = 3.15, P < 0.01, and
F(1,84) = 22.72, P < 0.001;
A gradual onset
and citalopram is shown in
2 weeks of
did not differ
either at a dose
10.54, P < 0.0021, or
of action of buspirone is
as no significant increase in
controls were observed
of the stress-
100135 [F(1,84) = 13.09;
with all the active
treatment with imipramine,
to the above drugs,
have no effect on the
sucrose consumption the
6 weeks of administration,
The present results confirm some earlier observations
that chronic mild stress (CMS)
reduction in the consumption
rats (anhedonia), and that this effect can be reversed by
repeated treatment with various
Among others, the CMS-induced
reported to be sensitive to a number
pramine and amitriptyline, as well as to the selective 5-HT
causes a substantial
of a 1% sucrose solution in
1308 E. Przegaliriski et al.
or NA uptake inhibitors fluoxetine and maprotiline (see
Willner et al., 1992). In this respect our results confirm the
above findings on imipramine (including the time-course
and the magnitude of its activity) and extend them to
another non-tricyclic selective 5-HT uptake inhibitor,
The main finding of the present study is, however, the
reversal of the CMS-induced
treatment with some 5-HTIA receptor
buspirone and WAY 100135, but not with 8-OH-DPAT
or ipsapirone. The magnitude of the effect of buspirone
and WAY 100135 is comparable
following similar administration of imipramine, although
the onset of action of both these compounds seems to be
slower than that of the tricyclic drug. It is also noteworthy
that the increase in the sucrose intake caused by buspirone
and WAY 100135 is specific to stressed animals; the
behaviour of non-stressed controls was not affected by
either treatment. This observation resembles the action of
all the antidepressant drugs tested in the CMS model of
depression, and corresponds well to the failure of these
drugs to elevate mood in non-depressed human subjects
(see Willner et al., 1992). The lack of effect of buspirone
and WAY 100135 on the consumption
solution in control animals also suggests that the action
of these compounds in stressed animals does not result
from their possible non-specific effects on the consumma-
tory behaviour. This is compatible with previous findings
showing that both the CMS-induced decrease in the
sucrose intake and the therapeutic effect of drugs active
in this model do not involve motivational, consummatory
or learning processes (see Muscat and Willner, 1992;
Willner et al., 1992).
The finding that buspirone can reduce the behavioural
deficit in the CMS model of depression confirms earlier
data obtained in other studies indicating that this drug
shares some properties with antidepressant
example, buspirone has been found to eliminate the
escape failure produced by an inescapable shock, i.e. in a
learned helplessness model (Drugan et al., 1987; Giral
et al., 1988) to attenuate the reduction of the locomotor
activity induced by restraint stress (Kennett et al., 1987)
and to decrease the immobility time in a forced swimming
test (Cervo and Samanin, 1987; Wieland and Lucki,
1990). Furthermore, it has also been reported
chronic administration of this drug down-regulates brain
5-HT2 receptors (Taylor and Hyslop, 199ltanother
effect characteristic for many antidepressant drugs. With
regard to the effect of WAY 100135 observed in our study,
this observation indicates
depressant properties of this compound, since such an
effect has not been tested in other models of depression
as yet. On the other hand, it should be underlined that
8-OH-DPAT and ipsapirone,
being inactive in the CMS model of depression, are active
in other animal tests used to detect
antidepressant properties, such as a forced swimming test
(Wieland and Lucki, 1990), learned helplessness (Giral
anhedonia by chronic
to that observed
of the sucrose
for the first time anti-
both these compounds
et al., 1988) and restraint-induced
(Kennett et al., 1987). The reason for this discrepancy is
unclear, though several differences between the exper-
imental conditions (duration
treatment, dosages, etc) used in our study and those
described by the above-cited
Antidepressant drugs are effective
endogenous depression, but also in some forms of anxiety
(Kahn and van Praag, 1992). At the same time, buspirone
is an anxiolytic drug (see Eison and Eison, 1994), and
WAY 100135 has also been reported to be active in an
animal model of anxiety (Rodgers and Cole, 1994).
However, a possibility that the anxiolytic properties of
buspirone and WAY 100135 are responsible for the
increase in the sucrose intake in stressed animals is
unlikely, since chlordiazepoxide,
anxiolytic, is ineffective in the CMS model (Muscat et al.,
1992), and the CMS procedure does not modify the level
of animal anxiety (D’Aquila et al., 1995).
The mechanism by which buspirone and WAY 100 135
produce an antidepressant effect in the CMS model is
unclear. Both these drugs have a high affinity for 5-HTIA
receptors, though they differ in terms of their intrinsic
activity. While buspirone is a partial agonist of these
receptors (i.e. it has agonistic activity at presynaptic
5-HTIA receptors and antagonistic or partially agonistic
activity at postsynaptic 5-HT,, receptors; see Glaser and
de Vry, 1992) WAY 100135 is a full antagonist of pre- and
postsynaptic 5-HTlA receptors, and is devoid of any
agonistic properties (Fletcher et al., 1993a; Routledge
et al., 1993; Przegaliiiski et al., 1994). Thus, from this
point of view, the antidepressant effect of buspirone and
WAY 100135 seems to be related to their antagonistic
rather than agonistic activity at (postsynaptic?) 5-HTIA
receptors, the more so as we have found that the full
agonist of these receptors 8-OH-DPAT (Middlemiss and
Fozard, 1983) administered chronically is inactive in the
CMS model. Although a similar lack of the effect of
ipsapirone, another mixed agonist/antagonist
receptors (Glaser and de Vry, 1992), demonstrated in our
study does not support the above conclusion, some other
issues seem to indicate possible links between the
antagonism at 5-HTIA receptors
activity: (i) the antidepressant
etoperidone, besides their well known 5-HT uptake
inhibiting and 5-HTz receptor blocking properties, were
recently reported to have a high affinity for 5-HTlA
receptors and to behave functionally as their antagonists
(Raffa et al., 1992); (ii) pindolol, a p-blocker with a potent
antagonistic activity at 5-HTIA receptors (Hoyer, 1991),
dramatically and rapidly improves the antidepressant
efficacy of selective 5-HT
monoamine oxidase inhibitors in depressed patients,
though this effect seems to result from the antagonism at
presynaptic 5-HTIA receptors
(iii) 5-HTIA antagonists may reduce the deficit in the
neocortical excitatory glutamatergic neurotransmission
and schedule of drug
authors should be
not only in
drugs trazodone and
uptake inhibitors and
(Artigas et al., 1994);
5-HTIA receptor ligands in an animal model of depression
(Fletcher et al., 1993b), and such a deficit is suggested to
be involved in depression (Francis et al., 1989); (iv) the
CMS procedure causes an increase in the density of
hippocampal 5-HTlA receptors
Although the latter effect is not modified by chronic
treatment with imipramine and thus argues against the
role of S-HTIA receptors in the anti-anhedonic effect of the
tricyclic drug, it does not exclude a possibility that
blockade of these receptors may be responsible for such
an action of other drugs (e.g. buspirone and WAY
It is now well established that the CMS-induced
anhedonia results from the impairment of functions of
postsynaptic D-2 receptors in mesolimbic structures, and
normalization of the functions of these receptors by
chronic administration of antidepressant
postulated to mediate their action in the CMS model
(Willner et al., 1991; Papp et al., 1994b). In this context
it is important to note that buspirone, besides its high
affinity for 5-HTIA receptors, also binds to D-2 receptors
(Riblet et al., 1982; Garattini et al., 1982; Wood et al.,
1983). Functionally, the drug behaves as an antagonist
of D-2 autoreceptors, but not of postsynaptic
receptors, and enhances dopaminergic neurotransmission
(McMillen et al., 1983; McMillen, 1985). Accordingly,
when given chronically, buspirone reduces the synthesis
of dopamine in the striatum (Tunnicliff et al., 1992), but
does not change the sensitivity of D-2 autoreceptors to the
inhibitory effect of apomorphine
hydroxylase (McMillen, 1985). At the same time,
repeated treatment with buspirone does not modify the
density of striatal postsynaptic D-2 receptors, but reduces
their density increased . by chronic administration
neuroleptics (McMillen, 1985). Whether or not this
dopamine-related activity of buspirone has any signifi-
cance for the function of postsynaptic D-2 receptors and,
in consequence, for its antadepressant effect, remains to be
further evaluated. In contrast to buspirone, WAY 100135
does not bind to D-2 receptors (Fletcher et al., 1993a),
and no data are available on the effect of chronic
administration of this compound on the brain dopamine
system, in particular on the function of postsynaptic D-2
In conclusion, our results show that of the 5-HTu
receptor ligands tested in this study, only buspirone
and WAY 100135 given chronically
reversing the CMS-induced anhedonia, resembling-at
least in terms of the magnitudethe
citalopram. Although further studies are necessary to
clarify the exact mechanism of action of buspirone and
WAY 100 135 in this model of depression, the antagonism
at 5-HTIA receptors
buspirone-the interaction with dopamine D-2 receptors
should be taken into account.
(Papp et al., 1994a).
on striatal tyrosine
are effective in
effect of similarly
drugs imipramine and
least in the case of
their generous gift of citalopram.
authors are grateful to Lundbeck for
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