Psychopharmacology (1997) 132 : 303310
© Springer-Verlag 1997
O R I G I NA L I N V E S T I G AT I O N
Frank Sams-Dodd · Barbara K. Lipska Daniel R. Weinberger
Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood Received: 12 December 1996 /Final version: 25 February 1997
Abstract The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of several aspects of schizophrenia. This lesion produces a number of behavioural abnormalities, such as hyperlocomotion and deÞcits in prepulse inhibition of startle, that present themselves relatively late in development, i.e. after puberty. Some of these abnormalities, which are thought to model the positive symptoms of schizophrenia, can be normalized by chronic treatment with neuroleptics. In the present study, we examined the e¤ects of the neonatal hippocampal lesion on social behaviour. Social withdrawal and isolation are key components of the negative symptoms of schizophrenia that have not been previously addressed in this model. Rats were lesioned on postnatal day 7 (PD7) and tested for social interaction on PD35 and PD65. They were then treated with clozapine (1.9 and 7.4 µmol/kg or 0.63 and 2.5 mg / kg) for 21 days and retested. The results show that although, as previously reported, spontaneous hyperlocomotion emerged in the lesioned rats only after puberty (PD65), social interaction deÞcits and behaviors that may reßect anxiety were present at both PD35 and PD65. Clozapine normalized locomotion, but did not ameliorate putative anxiety or social interaction deÞcits in the neonatally lesioned rats. Our results indicate that the neonatal hippocampal lesion in the rat models some aspects of both positive and negative symptoms of schizophrenia. The e¤ects of clozapine appear inconsistent with its putative beneÞt for negative symptoms.
F. Sams-Dodd (*) Pharmacological Research, H. Lundbeck A /S, Ottiliavej 9, DK-2500 Valby, Denmark Fax (+45) 3630-5267, e-mail:
[email protected] B.K. Lipska · D.R. Weinberger Clinical Brain Disorders Branch, IRP, NIMH, Neuroscience Center at St. Elizabeths, Washington, DC 20032, USA
Key words Hyperactivity · Hippocampus · Neonate · Negative symptoms · Positive symptoms · Rat · Schizophrenia · Social behaviour
Introduction Ibotenic acid lesion of the ventral hippocampus in neonatal rats has been proposed as an animal model of schizophrenia (Lipska et al. 1993). After puberty, rats with neonatal hippocampal lesions develop behavioural abnormalities, such as locomotor hyperactivity, supersensitivity to dopamine agonists and glutamate antagonists, deÞcits in startle response, i.e. behaviours thought to correspond to certain aspects of the positive symptoms of schizophrenia (Lipska et al. 1993, 1995; Lipska and Weinberger 1996). Long-term treatment with neuroleptic compounds ameliorates some of the abnormal behaviours in these rats (Lipska and Weinberger 1994). These Þndings have demonstrated that this animal model mimics certain aspects of the positive symptoms of schizophrenia. It is therefore of interest to extend these studies to the negative symptoms of schizophrenia, an aspect that has not been previously addressed. Negative symptoms represent behaviours that are reduced compared to the normal state and include social withdrawal, blunted a¤ect and poor rapport (Kay et al. 1987). These symptoms may appear earlier than the positive symptoms and tend to persist throughout the lifetime of the schizophrenic patient. Although both classical neuroleptic drugs, such as haloperidol, and the atypical neuroleptic drugs, such as clozapine, have been successful in treating positive symptoms, only clozapine seems to have superior e¦cacy on negative symptoms (Kane et al. 1988; Meltzer et al. 1991; McLaren et al. 1992; Breier et al. 1994). However, negative symptoms, even in responsive patients, are not cured by clozapine and some
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symptoms, e.g. most cognitive deÞcts (Goldberg et al. 1993) or eye-tracking abnormalities (Litman et al. 1994), are not a¤ected at all. Previous studies in rats have suggested that behaviours corresponding to certain aspects of positive and negative symptoms of schizophrenia can be assessed in the social interaction test (Sams-Dodd 1995a, 1996). In this behavioural model, PCP and other glutamate antagonists that in humans mimic both positive and negative symptoms of schizophrenia (e.g. Greifenstein et al. 1958; Davies and Beech 1960; Siegel 1978; Sveinbjornsdottir 1993), produce in the rat locomotor hyperactivity, stereotyped behaviour and social isolation. In contrast, d-amphetamine that induces psychotic episodes in humans (e.g. Bell 1965; Ellinwood 1967; Snyder 1973), induces in the rat locomotor hyperactivity and stereotyped behaviour without a¤ecting social behaviours. In this paradigm, chronic clozapine, but not haloperidol, partially normalizes PCP-induced stereotyped behaviour and social isolation. These Þndings have suggested that the social interaction test may be used to assess face as well as predictive validity of animal models of aspects of negative symptoms of schizophrenia. The purpose of the present study was to determine if rats with neonatal ibotenic acid lesions of the ventral hippocampus demonstrate deÞcits in their social behaviour before and after puberty, and whether these deÞcits can be alleviated by chronic treatment with clozapine. Thus, rats were lesioned with ibotenic acid on postnatal day 7 (PD7) and tested in the social interaction test on PD35 (pre-puberty) and PD65 (postpuberty). They were then treated with clozapine (1.9 and 7.4 µmol/kg or 0.63 and 2.5 mg / kg) for 21 days and retested for social interactions and locomotor activity. Our Þndings demonstrate that the neonatal hippocampal lesion models some positive as well as negative aspects of schizophrenia and that the onset of these symptoms resembles the clinical picture.
Materials and methods Animals Adult male and female Sprague-Dawley rats (Zivic Miller, USA) were housed in Macrolon type III cages in animal rooms at 21 ± 2°C with a relative humidity of 55 ± 5%, air exchange (16 times /h), and with a 12 h:12 h light/dark cycle, changing at 1800 hours and 0600 h. The rats had free access to water and commercial food pellets throughout the study.
Drugs and drug administration Ibotenic acid (Sigma, St Louis Mo., USA) was dissolved (5 mg / 500 µl) in artiÞcial cerebrospinal ßuid (pH 7.4) and approximately 10 µl of 1 N NaOH to adjust pH to 7.4. Aliquots of 50 µl were kept frozen in [80°C until used for infusion. Clozapine (mol. wt 327; Sandoz, s.a.) was dissolved in minimal amounts of acid, diluted
with saline and pH was adjusted to 7.4. Vehicle solution was 0.9 % NaCl. The solutions were Þltered with a Millix-HA Þlter (0.45 µm; Millipore Corp.), and the drugs were given subcutaneously (SC) in a volume of 5 ml / kg.
Surgical procedure Rat pups were lesioned as described previously (Lipska et al. 1993). On day 7 of age (PD7, weight 1520 g), the pups were anaesthetised by hypothermia (placed on ice for 15-20 min). An incision was made in the skin overlying the skull and 0.3 µl ibotenic acid solution (Sigma; 10 µg /µl) or artiÞcial cerebrospinal ßuid (in the sham-operated rats) was infused bilaterally into the ventral hippocampal formation at a rate of 0.15 µl /min using an infusion minipump. The co-ordinates were as following : AP [3.0 mm, ML ± 3.5 mm, VD [5.0 mm, relative to bregma. The pups were warmed and then returned to their mothers. On PD25-28, animals were weaned and separated according to the lesion status.
Experimental procedure Adult male and female Sprague-Dawley rats were imported from Zivic Miller Labs, USA and were placed in a normal daylight cycle. Three days after arrival a male and a female rat were placed together in a breeding cage. The cages were then inspected every morning and afternoon for mating plug to determine the day of conception. After the mating plug had been observed, the female rats were transferred to standard housing cages and were kept on food for breeding rats. All births occurred over a 4-day span. Female pups were removed from the cages immediately after birth. On PD7, male rats (n = 124) were randomly assigned to either sham (n = 50) or lesion (n = 74) treatment and received either vehicle or ibotenic acid injection into the ventral hippocampus. On PD 2528, the rats were removed from their mother and were placed in housing cages, three rats of the same status (lesioned or sham-operated) per cage. On PD 2830, half the rats from each group were dyed with white, and the other half were dyed with black hair colour on the rear part of the body. On PD 3536, they were all tested between 1900 hours and 2200 hours in the social interaction test. Following testing, the rats were placed in a reversed daylight cycle. On PD-5759, they were dyed again, and on PD 64 65, all rats were retested in the social interaction test between 0900 hours and 1300 hours. Approximately 2 weeks after the last testing, the sham and lesioned rats were randomly assigned to 22 days of daily drug administration with vehicle, 1.9 or 7.4 µmol /kg (0.63; 2.5 mg / kg) clozapine, SC. On day 21 of drug treatment (PD 94 99), the rats were tested between 0900 hours and 1300 hours in the social interaction test (pre-treatment time 45 min), and on day 22, in the motility test for 120 min (drug administered immediately prior to testing). In the social interaction test, no rat was ever tested with the same rat more than once. Following the last testing, the animals were killed and the brains were removed for veriÞcation of the lesion site.
Social interaction test A general design of the model was adapted from File (1980) and has been previously described in detail (Sams-Dodd 1995b, 1996). The test was performed in an open arena (l,w,h : 150 cm × 100 cm × 40 cm) with bedding of grey gravel. The gravel had been exposed to other rats before testing to provide a constant odour level in the arena. The behaviour of rats was recorded by a video camera (Cohou model 47222000 with Ernitec 6 mm /1.2 lens) that was placed above the arena and was connected to a S-VHS video cassette recorder. Lighting in the room consisted only of dark-red light (25 W bulbs) and was di¤use to minimise shadows in the arena. Three arenas were run in parallel and were started at the same time.
305 The white- and black-dyed rats were placed in the experimental room the day before testing. On the day of testing, all rats were weighed. One white and one black rat, that had received identical treatment and that were unfamiliar to each other, were placed simultaneously into the unfamiliar arena 8090 cm apart. Their behaviour was video Þlmed for 10 min whereafter the rats were returned to their home cages. Each 10-min observation period on the videotapes was analysed o¤-line by the EthoVision programme (version 1.63, Noldus Information Technologies, b.v.). The arena was scanned 3.1 times per second and the positions of rats were determined for each scanning. The co-ordinates were subsequently related to actual distances in the arena by a calibration of the programme to the dimensions of the arena. This analysis resulted in a track record for each rat that contained a complete record of the rats movement pattern in the arena during the observation period. This track record was analysed for the following parameters: Distance travelled (cm): Total distance travelled during an observation period. For this parameter only every sixth sample was used in order to minimise noise in the data. Percent time in central zone: Percentage of the 10-min observation period spend in the central zone by each rat. The arena was divided into a central and a peripheral zone that covered 33 % and 66% of the arena, respectively. Active and passive social interaction (s): Duration of social behaviour between the rats when the rat actively moved around in the arena or was inactive, respectively. Social interaction was measured for a sample n[12 by a hysteresis function with a lower threshold set at 20 cm and an upper threshold set at 25 cm. The active and passive movement states were deÞned by applying a hysteresis function to the average velocity of the rat over a sampling period of 24 samples (sample n[24 to n) with lower thresholds set at 1 and 3 cm/sec and upper thresholds were set at 4 and 6 cm / s for a white and a black rat, respectively. Finally, a nested analysis was conducted on these data to determine the duration of these behaviours (Observer 3.0, Noldus Information Technologies, b.v.). In addition, during each session rats were rated by a trained observer to determine if they displayed behaviours resembling damphetamine- and PCP-induced stereotyped behaviours and ataxia as a result of the neonatal lesion (see Sams-Dodd for details of the rating scales and procedures). However, the rats did not display any of these behaviours and these data have therefore been omitted.
ranging from 0 to 6. Representative sections for the di¤erent lesion scores are shown in Fig. 1. Subjects with unilateral or extrahippocampal damage were deleted from the analysis (n = 15).
Data and statistical analysis The statistical analysis was based on ANOVA with Fishers LSD post hoc test (two-tailed) and regression analysis. Prior to statistical analysis, the activity counts from the motility test were log-transformed and the lesion scores, which are of an ordinal type, were ranked (Huitema 1980). All data are presented as means with standard error of mean (SEM) and the statistical analysis was performed with Systat v. 5.2 (Macintosh version).
Motility test Locomotor activity was measured for 120 min in Macrolon type III (l,w,h: 37 cm × 22 cm × 19 cm) animal cages with sawdust bedding in a brightly lit room. Four sets of equally spaced photo diodes registered movements in the longitudinal direction of individual cages as the number of times the infrared light beams were interrupted. The activity counts would not increment if the same light beam was interrupted twice or more in a row without activation of other beams, thus preventing repetitive stationary movements from a¤ecting the activity counts. Registration and timing of locomotor activity was fully automated (custom-designed hardware and software).
Rating of lesion size Frozen brains were cut into 20 µm sections and Nissl-stained. The microscopic analysis of the hippocampal region was done blind to the status of the rat and the results of the behavioural studies. The extent of the lesion on each side of the brain was rated as follows : 0 no discernible cell loss in the hippocampal formation, 1 small, 2 medium, 3 large area of cell loss within the ventral hippocampal formation. Scores for both sides were added to yield a total score
Fig. 1A,B Lesion boundaries deÞned as the area of neuronal absence and determined from thionin-stained coronal sections from rats with neonatal (postnatal day 7) ibotenic acid lesions of the ventral hippocampal formation. Co-ordinates refer to distance in mm posterior to bregma. A Blackened areas indicate small lesion (score 1). B Blackened curves indicate a medium (score 2), and the blackened plus the striped area indicate a large lesion (score 3)
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Results Comparison of the lesion score (Fig. 2D) between the rats that had received artiÞcial cerebrospinal ßuid (sham group) or ibotenic acid injection (lesioned group) at PD 7 demonstrated that the ibotenic acid injection had produced a marked lesion of the ventral hippocampus [F(1,103) = 454.2; P < 0.001). The average lesion score for the ibotenic acid lesioned rats was 3.6 ± 0.23, indicating that the loss of hippocampal neurones was apparent in a restricted area of the ventral hippocampal formation including areas CA1CA3, portions of the dentate gyrus and subiculum (Fig. 1). In contrast to our previous reports (Lipska et al. 1993; Lipska and Weinberger 1995), there was minimal cavitation around the injection site. On average, this lesion was smaller than the one described previously. On PD35, the lesioned rats spent signiÞcantly less time in the central zone [F (1,88) = 19,6; P < 0.001] and were less engaged in active social interaction than sham-operated rats [F (1,88) = 33,3; P < 0.001], whereas both groups displayed similar levels of locomotor activity, i.e. distance travelled [F (1,88) = 0.52; P = NS], Fig. 2, and passive social interaction [F (1,88) = 0.4; P = NS] (data not shown). Regression analysis performed in the lesioned rats did not demonstrate a signiÞcant correlation between percent time in the central zone and lesion score (R = 0.05; T = [0.30;
Fig. 2AD E¤ects of lesioning the ventral hippocampus at postnatal day (PD) 7 on the behaviour of rats at PD35 and 65 in the social interaction test. The sham group at PD35 and 65 includes 25 pairs of rats, and the lesioned group includes 20 pairs of rats. AC Displays the results of testing in the social interaction test and D shows the average lesion scores of the sham and lesion groups. The asterisks indicate level of signiÞcance based on an ANOVA test: *P < 0.05; **P < 0.01; ***P < 0.001. Shamtreated, lesioned rats
P = NS). However, a weak negative correlation was found between lesion score and the level of active social interaction (R = 0.42; T = [2.89; P < 0.01), indicating that the more severe the lesion, the larger the deÞcit in social behaviour (data not shown). On PD65, i.e. after puberty, the lesioned rats again demonstrated a signiÞcant reduction in per cent time spent in the central zone [F (1,88) = 8.2; P < 0.01] and in active social interaction [F (1,88) = 29,5; P < 0.001), and had the same level of passive social interaction as the sham group [F (1,88) = 0.1; P = NS). However, at this postpubertal age, the lesioned rats also demonstrated a signiÞcantly increased level of locomotor activity [F (1,88) = 10.1; P < 0.01], indicating that they were hyperactive compared to sham-operated rats. Regression analysis performed in the lesioned rats again demonstrated a signiÞcant negative correlation between lesion score and active social interaction (R = 0.45; T = [3.14; P < 0.01), but no correlations between lesion score and distance travelled (R = 0.26; T = 1.66; P = 0.1) or lesion score and percent time in the central zone (R = 0.149; T = 1.66; P = NS) were found. Approximately 2 weeks later, the rats were randomly assigned to the drug treatment groups and began daily treatment for 22 days with vehicle, or 1.9 or 7.4 µmol/ kg (0.63; 2.5 mg / kg) clozapine. The post-hoc analysis of the lesion scores demonstrated that there were no di¤erences in the lesion scores between the
307 Fig. 3AD Dose-response of clozapine in the social interaction test and the motility test in adult rats subjected to lesioning of the ventral hippocampus at postnatal day 7. The lesioned groups included Þve to seven pairs of rats per dose and eight pairs in the sham-treated groups. AC Display the results of the social interaction test and D shows the locomotor activity in the motility test. The asterisks indicate level of signiÞcance relative to the vehicle-treated group and are based on an ANOVA test with a Fishers LSD posthoc test: *P < 0.05; **P < 0.01; ***P < 0.001. s Sham, , lesion
di¤erent dose groups [dose F (2,80) = 0.8; P = NS; treatment F (1,80) = 477.9; P < 0.001; dose versus treatment F (2.80) = 0.8; P = NS]. On PD96, after 21 days of drug administration, the rats were then retested in the social interaction test (Fig. 3AC), and again in motility cages after 22 days of treatment (Fig. 3D). In the social interaction test, signiÞcant e¤ects of dose and treatment (i.e., sham or lesion) were found for distance travelled [dose F (2,80) = 13.1; P < 0.001; treatment F (1,80) = 8.0; P < 0.01; dose versus treatment F (2,80) = 3.3; P < 0.05], percent time spent in the central zone [dose F (2,80) = 8.6; P < 0.001; treatment F(1,80) = 21.3; P < 0.001; dose versus treatment F (2,80) = 0.01; P = NS] and active social interaction [dose F (2,80) = 10.9; P < 0.001; treatment F (1,80) = 22.7; P < 0.001; dose versus treatment F (2,80) = 4.4; P < 0.05]. There was a signiÞcant e¤ect of dose, but not treatment for passive social interaction [dose F (2,80) = 3.4; P < 0.05; treatment F (1,80) = 2.7; P = NS, dose versus treatment F (2,80) = 3.1; P = 0.051]. Fishers LSD post-hoc test revealed that the lesioned rats treated with vehicle were hyperactive relative to the sham-operated rats and spent less time in the central zone. These e¤ects had been previously seen on PD65. However, the deÞcit in active social interaction in the lesioned vehicle-treated group, that had been observed
at PD35 and 65, was no longer signiÞcant on PD96. Clozapine dose-dependently reduced distance travelled and percent time spent in the central zone in the shamoperated rats. Moreover, it increased passive and had no e¤ect on active social interaction in the sham rats. In the lesioned rats, both doses of clozapine were equipotent in reducing locomotor hyperactivity to the level of the vehicle-treated, sham-operated rats. In addition, clozapine dose-dependently reduced percent time spent in the central zone and the level of active social interaction, but did not a¤ect passive social interaction in the lesioned animals. Finally, the rats were tested in the motility test for 120 min. SigniÞcant e¤ects of dose and treatment on locomotion were observed in this test [dose F (2,97) = 8.1; P < 0.001; treatment F (1,97) = 12.2; P < 0.001; dose versus treatment F (1,97) = 0.2; P = NS]. The vehicle-treated lesioned rats were hyperactive relative to the vehicle-treated sham controls. Moreover, a positive correlation between the locomotor activity level and lesion score for the vehicle-treated lesioned rats was found (R = 0.49; T = 2.34; P < 0.05). Clozapine dose-dependently reduced locomotor activity of the sham-operated rats, but the two doses were equally potent in reducing locomotion of the lesioned rats to the level of vehicle-treated sham controls.
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Discussion The results of this study demonstrate that ibotenic acid lesions of the ventral hippocampus in neonatal rats produce deÞcits in social behaviour that are present both prior to and after puberty, and locomotor hyperactivity that emerges only after puberty. In addition, the study shows that chronic treatment with clozapine reduces hyperlocomotion of adult lesioned rats to the level of the vehicle-treated controls, but also dosedependently potentiates social interaction deÞcits and exaggerates behaviours that may reßect anxiety (i.e. per cent time spent in the central zone). When analysing the behavioural data from the social interaction test, it is important to consider the possibility that di¤erent behavioural parameters are not independent of each other. For example, the deÞcits in social interaction may be indirectly caused by an anxiogenic e¤ect of the lesion since percent time spent by the lesioned rats in the central zone of an open arena is also signiÞcantly decreased. This e¤ect is even more apparent after clozapine, which seems to reduce all behavioural parameters in the lesioned rats. Another possibility is that the lesioned rats actively avoid each other, so they maximize the distance between themselves by spending more time in the periphery of an open Þeld. Social interactions are, however, completely dissociated from the central zone exploration in the sham-operated rats, since following clozapine, these animals display unchanged levels of active social interaction and increased levels of passive social interaction while, at the same time, they increasingly avoid the central zone. A similar argument can be made for the dissociation of locomotor activity from social interaction in both lesioned and sham-operated rats, suggesting that each of the behavioural parameters seems to be independent of each other and may be used to analyse di¤erent aspects of behaviour in rats. The present data demonstrate that the lesioned rats display deÞcits in their social behaviour at PD35 and PD65, but that these deÞcits are no longer apparent at PD96. In contrast, locomotor hyperactivity emerges only after puberty and persists until at least PD96. This latter Þnding has been recently conÞrmed in another study (Black et al. 1996). The fact that the deÞcits in active social interaction are no longer signiÞcant in the lesioned rats by PD96 may suggest compensatory changes occurring with ageing. This interpretation should, however, be made with caution, because the relatively small deÞcits (approximately 20 % reduction) might have not been detected merely due to the small sample size in this Þnal test (n = 8 and Þve pairs of sham and lesioned rats, respectively, as compared to 20 and 25 pairs tested at younger ages). Another confound might be repeated testing since the rats at PD96 were tested for the third time in the same arena. Therefore, the conclusion about the putatively time-limited e¤ects of the lesion on social deÞcits drawn from this study
should be treated with caution, and the study should be replicated in a larger cohort of rats. Finally, the results also suggest that the neonatal lesion produces persistent anxiety, since the lesioned rats spend consistently less time in the central zone of an open Þeld at all ages tested. Our data from clozapine treatment in the social interaction test suggest that clozapine may exert a somewhat speciÞc e¤ect on ameliorating hyperlocomotion of the lesioned rats, since both doses are equally potent in normalizing locomotion in these animals (i.e. clozapine-treated lesioned rats moved as much as the vehicle-treated controls); while, in contrast, control animals display more dramatically reduced locomotion after clozapine and this e¤ect is dose-dependent. A beneÞcial e¤ect of clozapine on lesion-induced deÞcits in social behaviour could not be determined, since this lesion e¤ect could not be replicated at PD96. However, the data showed that clozapine itself produced a dosedependent decrease in the level of social behaviour in the lesioned rats, which was not reßected in the control groups. The behavioural abnormalities observed in the present study, which have been proposed as putative models of positive symptomatology (i.e., hyperlocomotion), and the e¤ects of chronic clozapine treatment on hyperlocomotion are consistent with previously reported Þndings both with respect to the nature of the behavioural deÞcit and its time of onset during development (Lipska et al. 1993, 1995; Lipska and Weinberger 1994). However, comparisons with previous studies indicate that the size of the lesioned area in this study was smaller (Lipska et al. 1993, 1995; Lipska and Weinberger 1994, 1995). Apart from these minor di¤erences in size of lesion, we conÞrmed the earlier Þndings in a di¤erent laboratory using the social interaction test instead of standard locomotor activity cages. Independent replications of some aspects of the model have recently been reported elsewhere (Black et al. 1996; Flores et al. 1996). It should also be noted that the e¤ects of the neonatal ibotenic acid lesion, although weaker in intensity, are qualitatively similar in this test to the e¤ects of phencyclidine, a psychotomimetic compound, that induces some aspects of both positive and negative symptoms in humans (e.g. Siegel 1978), and hyperactivity and social isolation in rats (Sams-Dodd 1996). Longitudinal studies of schizophrenic patients have indicated that pre-schizophrenics in many cases demonstrate di¦culty in establishing normal relations with other people and may avoid contact with their peers at school (Neuechterlein 1986; Auerbach et al. 1993; Done et al. 1994; Jones et al. 1994). This has been interpreted as early signs of negative symptoms and has suggested that this group of symptoms may be present very early in schizophrenic patients. In contrast, the positive symptoms appear to develop during early adulthood, and the Þrst acute psychotic episodes
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normally occur around age 1825 in humans (e.g., Eaton et al. 1995). Interpreting the results of the present study in this context suggests that the behavioural deÞcits observed in the neonatally treated rats closely resemble this clinical pattern. To the extent that deÞcits in social behaviour and locomotor hyperactivity correspond to some aspects of the negative and positive symptoms of schizophrenia, respectively, these data indicate that this animal model in many aspects mimics schizophrenia both with respect to phenomenology and to the temporal pattern of symptom onset, i.e. it may have both face and construct validity (for discussion, see Weinberger and Lipska 1995). However, it seems to lack predictive validity in terms of the responsivity of the negative symptoms to atypical neuroleptic treatment, since the clozapine data seem inconsistent with the putative beneÞcial e¤ects of this drug in schizophrenic patients. In conclusion, the results of the present study indicate that rats with neonatal ibotenic acid lesions of the ventral hippocampus display deÞcits in their social behaviour prior to and after puberty, whereas spontaneous hyperlocomotion emerges only in adolescence. An interpretation of the results in the context of the neurodevelopmental hypothesis of schizophrenia suggests that neonatal hippocampal lesion in the rat models some positive as well as negative aspects of this disorder, and that the onset of behavioral abnormalities in this model closely resembles a clinical pattern. Further research is needed to determine the time course of these behaviours during a rats life span as well as their responsivity to a wider range of antipsychotic medications. Acknowledgements We thank Ms. Marit Pedholt Larsen, Ms. Pi Ørum and Mr. Richard Urbina for their technical assistance in conducting these experiments, and Dr. Jørn Arnt for valuable comments on the manuscript.
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