Behavioral and Neurochemical Differences Between Fischer 344 and Harlan–Wistar Rats Raised Identically

Behavior Genetics, May 1999

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.

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Behavioral and Neurochemical Differences Between Fischer 344 and Harlan–Wistar Rats Raised Identically

Behavior Genetics 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 INTRODUCTION 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 behavioral patterns. 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 the X-maze. 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 Harlan-Wistar rat). 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 compartment. 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 recorded. 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 histologically determined. 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). DISCUSSION 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. Andrews , J. 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A. Rex, J.-P. Voigt, H. Fink. Behavioral and Neurochemical Differences Between Fischer 344 and Harlan–Wistar Rats Raised Identically, Behavior Genetics, 1999, 187-192, DOI: 10.1023/A:1021644002588