Behavioral and Neurochemical Differences Between Fischer 344 and Harlan–Wistar Rats Raised Identically
Behavioral and Neurochemical Differences Between Fischer 344 and Harlan-Wistar Rats Raised Identically
A. Rex 1 2
J.-P. Voigt 1 2
H. Fink 0 2
0 Institute of Pharmacology and Toxicology, School of Veterinary Medicine, Free University of Berlin , Koserstr. 20, D-14195 Berlin, Germany. macology and Toxicology , Humboldt-University , D-10098 Berlin, Germany. Fax:
1 Institute of Pharmacology and Toxicology , Charite , Medical Fac- ulty, Humboldt University at Berlin , D-10098 Berlin , Germany
2 Rex , Voigt, and Fink
Inbred Fisher 344 and outbred Harlan-Wistar rats were compared in the elevated plus maze, the black-and-white box, the social interaction test, and a modified open-field test, to assess the contribution of genetic factors to aversion-motivated behavior. All animals used were born and raised under identical conditions. Compared to the Wistar rats, the Fischer rats displayed a more pronounced fearful behavior in all tests. In a separate microdialysis study, the relationship between behavioral variations to biochemical differences was assessed, with serotonin (5-HT) release in the ventral hippocampus being measured during the elevated plus-maze test. Exposure to the elevated plus-maze induced an increase in hippocampal 5-HT in the (more anxious) Fischer rats but not in the (less anxious) Wistar rats. The results confirm the influence of genetic factors on emotionality in rats and demonstrate a close, although not simple, relationship between the serotonergic system and "anxiety-related" behavior.
Anxiety; genetic differences; microdialysis; serotonin; elevated plus-maze test; black-andwhite box test; social interaction test; modified open-field test
Studies in behavioral pharmacology have often shown
different, and sometimes contradictory, results using
the same animal model of "anxiety" and identical test
procedures (e.g., Griebel, 1995; File, 1996).
Differences in the behavioral reactions of untreated animals
to the test stimuli may be one reason for this, as well
as for discrepant responses to anxiolytic drugs (Rodgers
and Johnson, 1996).
In a previous study, we assessed the anxiety-related
behavior of rats acquired from different breeders,
finding that they showed a dissimilar, basal behavior in
various tests (Rex et al., 1996). As studies with mice have
shown that strain differences, as well as environmental
conditions maintained by the breeder/vendor, may
influence anxiety-related behavior (Trullas and Skolnick,
1993), we decided in the present study to minimize
environmental effects prior to conducting such tests with
rats from two stocks known for their divergent
Fischer 344 (inbred) and Harlan-Wistar (outbred)
rats, born and raised in our animal unit under
identical conditions, were tested in the following anxiety
tests based on native behavioral responses of rodents
to a novel and aversive environment: (1) a modified
open-field test, based on novelty-suppressed feeding
(Rex et al., 1998); (2) the social interaction test with
an unfamiliar partner (File, 1984, 1992), under
brightlight conditions; (3) the elevated plus maze (X-maze)
test (Pellow et al., 1985); and (4) the two-compartment
black-and-white box test, which also tests the aversion
of rodents to novel and brightly lit areas (Crawley, 1981).
Serotonin (5-HT) is considered to be a major
neurotransmitter in anxiety-related behavior, in both
animals and humans (e.g., Chopin and Briley, 1987). Drugs
acting at various serotonergic receptors, either
decreasing or increasing the activity of the central serotonergic
system, have "anxiolytic" or "anxiogenic" effects in
animals and humans, respectively (De Vry, 1995; Griebel,
1995). Exposure of animals to the aversive elevated
plus maze or the social interaction test causes an
increase in hippocampal 5-HT release, as monitored by
microdialysis (Cadogan et al., 1994; Wright et al.,
1992; Voigt et al., 1999). This rise in extracellular
5HT could be attenuated by the administration of
anxiolytic drugs (e.g., diazepam) before exposure to the
test (Cadogan et al., 1994, Rex et al., 1993). In
addition to studying genetic influences on anxiety-related
behavior, the present study sought to determine whether
they might reflect biochemical differences, i.e.,
differences in 5-HT release under aversive conditions, in
Animals. The rats used in this study were born and
raised in our animal unit, with the pregnant mothers
[22-28 weeks old; Harlan-Wistar rats from Harlan
-Winkelmann (n = 15) and Fischer 344 rats from
Charles River (n = 20)], purchased 14 days
postconception and housed in single cages. After weaning
(day 21), the rat pups were sorted by gender and
assigned to groups of five, with the litters split. For this
study only male rats 250 ± 30 g (aged 7-11 weeks) were
group-housed, five rats per cage (45 x 60 x 25 cm) and
kept under a 12-h light-dark schedule (lights on at
0600), with food (Altromin 1326) and water freely
available. All tests were performed in sound-attenuated
chambers between 0900 and 1100 (microdialysis
experiments also started at about 0900). Fischer and
Wistar rats were assigned randomly to the procedure. The
group size was 8-10 animals.
Modified Open-Field Test. Rats were food-deprived
for 20 h before testing, with water still available. The
rats were placed into a corner of a brightly illuminated
(1000-lux) white open field (100 x 100 x 40 cm),
containing familiar food in the center. Each rat was
observed for 5 min and the incidence of food intake
(percentage of rats in a group feeding), the time the animals
spent in the inner area (50 x 50 cm) of the open field
(seconds), the locomotor activity (meters), and the
number of rearings were registered (for more details
see Rex et al., 1998).
Social Interaction Test. Two rats from different
established groups of the same strain were placed in
opposite corners of the brightly lit (1000-lux) open
field described above. Each pair of rats was observed
for social contact for 10 min and the latency until the
first contact (seconds), the frequency (n/10 min), and
the cumulative duration of contact (seconds) were
determined (File and Hyde, 1978). Social contact
included following the unfamiliar partner, sniffing,
genital investigation of the partner, and climbing on or
crawling under the partner.
X-Maze Test. The behavioral experiments were
performed using an X-maze: height, 70 cm; arm length,
45 cm; arm width, 15 cm; and wall height on two
opposite arms, 10 cm. The X-maze was brightly
illuminated (~500 lux) to increase aversiveness. The rats were
placed in the center of the X-maze facing a corner of
the center platform. The experiments were performed
for 5 min (Pellow et al., 1985; Rodgers and Cole, 1994).
The behavioral parameters measured were entries into
the open arms, time spent in the open arms, time spent
in immobilization without visible movement of the
animals (Goldstein et al., 1996) at the beginning of the
test (measure of fear), and distance traveled
(locomotor activity). Rats which fell off the X-maze (n = 3)
were excluded from the study (two Fischer rats, one
Black-and-White Box Test. Testing was conducted
in a dimly (red lamp) illuminated room, using a
twocompartment box, for 10 min (Costall et al., 1989).
Only the white compartment was brightly lit. The test
box (65 x 39 x 39) was open-topped and was divided
into a (two-fifths) black-painted section, illuminated red
(1 x 40 W), and a (three-fifths) section painted white,
which was brightly illuminated (1 x 23-W Dulux EL).
Both red and white light sources were located 10 cm
above the test box, without "cross-lightning" between
the two sections. The indirect luminous intensity was
measured in the red-lighted area as 60 lux and in the
brightly illuminated section as 250 lux. The
compartments were connected by an opening 10 x 12 cm in
the dividing wall (39 cm high), located at floor level
in the center. The rats were placed into the center of
the white section, facing away from the opening in the
partition, and were observed by remote video
recording. Parameters measured were time spent in both
compartments, latency of the first movement from
white to black and latency of the first reentry into the
white area, transitions between the two compartments,
and stretched attend postures (SAP) into the white
Microdialysis on the X-Maze. Five days before the
experiment the rats were anesthetized using
pentobarbitone (45 mg/kg). A microdialysis-guide cannula was
stereotaxically implanted into the ventral
hippocampus [coordinates: AP = -5.6 mm, ML =4.7 mm from
the bregma, and depth = 7.5 mm from the brain
surface (Paxinos and Watson, 1986)] and fixed to the
skull using small screws and dental cement.
Following surgery the animals were allowed to recover.
Twenty-four hours before the experiment the
microdialysis probe (CMA 12; CMA/Microdialysis AB,
Sweden; outer diameter, 0.5 mm; length of the
dialysis membrane, 2.0 mm; cutoff point, = 20,000 daltons)
was inserted into the guide cannula and perfused using
artificial cerebrospinal fluid (CSF; 0.3 ul/min)
containing 5 mM glucose, 125 mM NaCl, 27 mM NaHCO3,
2.5 mM KCl, 0.5 mM NaH2PO4, 1.2 mM Na2HPO4,
0.5 mM NaSO4, 1 mM MgCl2, and 1 mM CaCl2. Two
hours before the begin of the experiment the flow of the
artificial CSF was increased (1 ul/min).
Microdialysis samples (20 ul) were taken every
20 min and analyzed immediately using HPLC with
electrochemical detection (Biometra) with a glassy
carbon electrode set at + 0.65 V versus an Ag/AgCl
reference electrode (Antec VT03). The stationary phase
was a 10-cm HPLC microbore-column (1-mm i.d.)
filled with Spherisorb ODS 2 (3 um). The isocratic
mobile phase contained 0.15 M NaH2PO4-2H20, 1.0 mM
EDTA, 0.25 mM sodium octanyl sulphonate, and 4%
isopropanol, adjusted to pH 3.8 using phosphoric acid.
The flow rate of the mobile phase was 50 ul/min at a
pressure of approximately 100 bar. When the 5-HT
concentrations reached stable levels, three samples for
the determination of basal extracellular 5-HT and
5hydroxy-3-indole-acetic acid (5-HIAA) were analyzed,
after which the rats were placed in the center of the
Xmaze for 20 min and the dialysate was collected
during this time (one sample). On exposure to the X-maze
the animals were observed and their behavior was
After 20 min the animals were removed from the
X-maze and for the subsequent 160-min dialysis
samples were collected in the home cage. Only one
animal per day was examined, and rats from both groups
were assigned to the procedure randomly. Following
termination of the study, the brains of the animals were
removed and fixed in 10% formalin, and the
implantation site of the microdialysis probe was
Statistics. The nontransformed data from the
modified open-field test were analyzed using Fisher's exact
probability test and were expressed as the percentage
of rats from each group feeding in the open field. All
other data, shown as means ± SE, were analyzed using
Welch's t-test. In vivo microdialysis data were analyzed
using a two way repeated-measures ANOVA followed
by the post hoc Tukey's test. Differences were
considered to be statistically significant at p < .05.
Modified Open-Field Test. Eight of ten Harlan
Wistar rats ate food in the aversive open field, whereas
none of the Fischer rats started feeding under these
conditions. The Harlan-Wistar rats also spent more time
in the inner area (25%) of the open field compared to
the Fischer rats. Both groups did not differ in the
numbers of rearings, but the Harlan-Wistar rats had a higher
locomotor activity (Table I).
Social Interaction Test. In the social interaction
test the Harlan-Wistar rats tended to make contact with
the unfamiliar partner earlier, showed a higher
frequency of contact, and spent more time in active social
contact than did the Fischer rats, which tended to make
contact later, showed a lower frequency of contact, and
spent less time in contact (Table I).
X-Maze Test. Harlan-Wistar rats spent more time
in the open arms and entries were directed into the open
arms more frequently than the Fischer rats. The
immobilization time (the time the animals remained frozen
following the placement on the X-maze) was
significantly higher in the Fischer rats than in the Harlan
Wistar rats (Table I).
Black-and-White Box Test. Harlan-Wistar rats
spent more time in the white area and needed less time
to reenter the white area than did the Fischer rats.
Both Harlan-Wistar and Fischer rats probed equally
often (SAP) into the white compartment without
leaving the darker part, but the Harlan-Wistar rats showed
more transitions between the two compartments than
did the Fischer rats (Table I).
Microdialysis on the X-Maze. Although there were
no differences in basal hippocampal 5-HT release
between the Fischer rats (18.8 ± 5.6 fmol/20 ul dialysate)
and the Harlan-Wistar rats (14.7 ± 4.0 fmol/ 20 ul
dialysate), exposure of the Fischer rats to the X-maze
resulted in an increase in extracellular 5-HT release in
the hippocampus of 142 ±7% compared to basal
levels. When the animals were returned to their home cage,
the release of extracellular 5-HT returned to
preexposure levels within 20 min. In the Harlan rats, exposure
to the X-maze did not cause any alterations in 5-HT
release (Fig. 1).
Levels of the 5-HT-metabolite, 5-HIAA, did not
change during the experiments in either group of rats.
a Data were analyzed using Welch's t test and are expressed as means ± SE.
* p < .05 compared to Fischer rats (n = 10).
In a previous study, rats from several strains/stocks
obtained from different vendors were tested for
potential differences in "anxiety"-related behavior. The
Fischer 344 rats, obtained from Charles River,
Germany, and the Wistar rats, supplied by
Harlan-Winkelmann, Germany, showed "opposite" baseline levels of
Fig. 1. Extracellular release of 5-HT in the ventral hippocampus of Fischer 344 (C; n = 8) and Harlan-Wistar (O; n = 8) rats. Data are
expressed as mean ± SE and were analyzed with a two-way repeated-measures ANOVA followed by a post hoc Tukey's test. *p < .05 compared
to Harlan-Wistar rats.
behavior in the modified open-field test and the
social interaction test, with the Fischer rats appearing to
be more "fearful" than the Harlan-Wistar rats (Rex
et al., 1996). Similar differences among stocks of rats
have also been described in the assessment of
cognitive behavior (e.g., Andrews, 1995) and in learned
helplessness behavior (Wieland et al., 1986), to name
only a few examples. Since the animals used in these
studies were obtained from different vendors, the
possibility exists that some of the differences seen were
caused by breeding conditions or differences in
handling or housing (Wright et al., 1991; Wongwitdecha
et al., 1996). We therefore decided to compare the
inbred Fischer 344 and outbred Wistar rats in question
using animals which were bred and raised in our
animal unit. Raised under identical conditions, they still
differed noticeably in anxiety-related behaviors and
in exploratory behavior. In the modified open-field
test the Harlan-Wistar rats explored more than the
Fischer 344 rats did, crossing into the center of the
open field with feeding in the aversive surroundings,
a behavioral pattern usually seen after after the
application of anxiolytic drugs in this test (Rex et al.,
1998). In the social interaction test, clear and reliable
differences between them were observed, with the
Harlan-Wistar rats spending more time in social
contact, as well as initiating social contact earlier and
more often than the Fischer 344 rats in the unfamilar
open field under bright-light conditions. On the
Xmaze the Harlan- Wistar rats displayed more entries
into the aversive open arms and spent more time in
the open arms. They also showed practically no
initial freezing following placement on the X-maze,
compared to the Fischer 344 rats. Comparable differences
in anxiety-related behavior between Wistar and
Fischer 344 rats have been demonstrated previously in
the social interaction test (Berton et al., 1997) and
analogous behavioral diversities between Fischer 344
and Wistar rats have been described in cognitive
behavior (Higashida and Ogawa, 1987; van der Staay
and Blokland, 1996) and in other behavioral tests
(Wieland et al., 1986; Armario et al., 1995; Lahmame
and Armario, 1996; Nakagawara et al., 1997). In the
black-and-white box, similar differences could be seen
in anxiety-related behavior between the Fischer and
the Harlan-Wistar rats, with the Wistar rats spending
more time in the aversive white compartment as well
as travelling earlier (latency to first reentry into the
white) and more often than the Fischer 344 rats into
the bright-lit white area. However, Harlan-Wistar rats
escaped more quickly from the white compartment for
the first time, supposedly an indicator of fear. One
possible explanation for this obvious discrepancy is that
the exploratory behavior of "anxious" rats will be
more susceptible to the aversive character of the white
compartment of the black-and-white box. Since this
compartment serves as the start compartment,
emotionally reacting rats like Fischer rats may initially
respond with an inhibition of exploratory behavior. In
future experiments, therefore, it might be more
"ethological" to place the animal in the dark area initially
and to measure the latency until the first entrance into
the aversive white area (Steimer et al., 1997).
Based on the often proposed relationship between
fear/anxiety and the central serotonergic system (Chopin
and Briley, 1987; Marsden et al., 1993), it is possible
that the suspected genetic differences between these
rats may be associated with differences in the activity
and/or function of the serotonergic system, e.g., either
in the mechanisms involved in 5-HT release or
reuptake, in the receptor or receptor subtype distribution,
or in polymorphisms of 5-HT receptors. To explore a
possible connection between the serotonergic system
and anxiety-related behavior, animals from both groups
were exposed to an aversive situation (X-maze)
combined with in vivo microdialysis measurement. The
observation time on the X-maze was prolonged to 20 min
to allow parallel determination of eventual alterations
in the level of hippocampal extracellular 5-HT, which
evidence suggests is of neuronal origin and reflects
terminal 5-HT release (Carboni and Di Chiara, 1989;
Lawrence and Marsden, 1992).
Exposure of the Fischer 344 rats to the X-maze
resulted in a significant, short-lasting increase in
hippocampal extracellular 5-HT, whereas 5-HT levels
remained constant in the less fearful Harlan-Wistar rats.
The exposure of rats to aversive conditions, e.g., the
social interaction test, the X-maze, or the Vogel test,
often leads to an increase in extracellular 5-HT, e.g.,
in the hippocampus (Wright et al., 1992; Cadogan et al.,
1994; Matsuo et al., 1996; Voigt et al., 1999). In the
present study, the association of anxious behavior with
increased 5-HT release, compared to "nonanxious"
behavior without an increase in extracellular 5-HT,
indicates that there may be a relationship between 5-HT
release and behavior indicative of anxiety, a finding
which is reinforced by the work from Schwarting et al.
(1998), which measured different 5-HT tissue levels in
discrete CNS areas in rats showing high and low
anxiety on the X-maze.
This work was supported by BMBF 01 ZZ 9511.
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