Behavioral characterization of mice lacking the neurite outgrowth inhibitor Nogo-A.

The membrane protein Nogo-A inhibits neurite outgrowth and regeneration in the injured central nervous system, primarily because of its expression in oligodendrocytes. Hence, deletion of Nogo-A enhances regeneration following spinal cord injury. Yet, the effects of Nogo-A deletion on general behavior and cognition have not been explored. The possibility of potential novel functions of Nogo-A beyond growth inhibition is strongly suggested by the presence of subpopulations of neurons also expressing Nogo-A - not only during development but also in adulthood. We evaluated here Nogo-A(-/-) mice in a series of general basic behavioral assays as well as functional analyses related to brain regions with notable expression levels of Nogo-A. The SHIRPA protocol did not show any major basic behavioral changes in Nogo-A(-/-) mice. Anxiety-related behavior, pain sensitivity, startle reactivity, spatial learning, and associative learning also appeared indistinguishable between Nogo-A(-/-) and control Nogo-A(+/+) mice. However, motor co-ordination and balance were enhanced in Nogo-A(-/-) mice. Spontaneous locomotor activity was also elevated in Nogo-A(-/-) mice, but this was specifically observed in the dark (active) phase of the circadian cycle. Enhanced locomotor reaction to systemic amphetamine in Nogo-A(-/-) mice further pointed to an altered dopaminergic tone in these mice. The present study is the first behavioral characterization of mice lacking Nogo-A and provides significant insights into the potential behavioral relevance of Nogo-A in the modulation of dopaminergic and motor functions.

Amphetamine sensitization in rats as an animal model of schizophrenia.

Based on the 'endogenous dopamine sensitization' hypothesis of schizophrenia the present study employed a repeated amphetamine administration regime in order to investigate the behavioral, neurochemical and neuroanatomical consequences following short- and long-term withdrawal periods. The escalating amphetamine administration schedule consisted of three injections per day over a 6-day period with the dosage ranging from 1 to 8 mg/kg. It was demonstrated that following both short- (4 days) and long-term (66 days) withdrawal periods latent inhibition (LI) and prepulse inhibition (PPI), two translational paradigms highly relevant to schizophrenia, were disrupted. A challenge injection verified sensitization in two different cohorts of animals at 40 and 70 days following cessation of treatment. Neurochemical evaluation demonstrated a reduction in dopamine levels in the caudate-putamen and nucleus accumbens core and shell as well as an enhanced utilization ratio in the caudate-putamen after both withdrawal periods. Similar to the findings from post-mortem studies of brains of schizophrenic patients, a downregulation of glutamic acid decarboxylase 67 (GAD67) immunoreactivity was found in the hippocampus, prefrontal cortex, thalamus, and amygdala in amphetamine pretreated animals following longer withdrawal periods. This was not accompanied by enhanced neurotoxicity or reactive gliosis as demonstrated by the immunohistological analysis using the apoptotic marker activated Caspase-3 and GFAP (glial fibrillary acidic protein; a marker for astrocytes) following both short- and long-term withdrawal periods. In conclusion, it is suggested that these findings constitute a highly reliable and valid animal model of schizophrenia.

Startle and prepulse inhibition as a function of background noise: a computational and experimental analysis.

Schmajuk and Larrauri [Schmajuk NA, Larrauri JA. Neural network model of prepulse inhibition. Behav Neurosci 2005;119:1546-62.] introduced a real-time model of acoustic startle, prepulse inhibition (PPI) and facilitation (PPF) in animals and humans. The model assumes that (1) positive values of changes in noise level activate an excitatory and a facilitatory pathway, and (2) absolute values of changes in noise level activate an inhibitory pathway. The model describes many known properties of the phenomena and the effect of brain lesions on startle, PPI, and PPF. The purpose of the present study is to (a) establish the magnitude of startle and PPI as a function of pulse, prepulse, and background intensity, and (b) test the model predictions regarding an inverted-U function that relates startle to the intensity of the background noise.

Withdrawal from repeated amphetamine administration leads to disruption of prepulse inhibition but not to disruption of latent inhibition.

The present study represents a continuous effort to develop an animal model of schizophrenia based on the "endogenous dopamine sensitization" hypothesis. To achieve this goal, withdrawal from an escalating amphetamine (AMPH) regime administration [three injections per day over a period of 4 days and increasing doses from 1 to 10 mg/kg of AMPH or an equivalent volume of saline (SAL)] was employed. Animals exposed to this treatment were evaluated on their performance in attentional (Latent inhibition, LI) and sensorimotor gating (Prepulse inhibition, PPI) tasks in a drug free state and tested for locomotor sensitization following a low dose of AMPH challenge administration.LI using active avoidance, tested on withdrawal day 4, was unaffected. PPI of the acoustic startle response, measured on withdrawal days 6 and 70, was disrupted. On the 76th day of withdrawal, a low challenge dose of AMPH (1 mg/kg) led to a clear locomotor sensitization effect.

Hippocampal alpha5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition.

Prepulse inhibition (PPI) refers to the phenomenon in which a low-intensity prepulse stimulus attenuates the reflexive response to a succeeding startle-eliciting pulse stimulus. The hippocampus, among other structures, is believed to play an important role in the modulation of PPI expression. In alpha5(H105R) mutant mice, the expression of the alpha5 subunit-containing GABA(A) receptors in the hippocampus is reduced. Here, we report that PPI was attenuated, and spontaneous locomotor activity was increased in alpha5(H105R) mutant mice. These effects were apparent in both genders. Thus, alpha5 subunit-containing GABA(A) receptors, which are located extrasynaptically and are thought to mediate tonic inhibition, are important regulators of the expression of PPI and locomotor exploration. Post-mortem analyses of schizophrenia brains have consistently revealed structural abnormalities of a developmental origin in the hippocampus. There may be a possibility that such abnormalities include disturbance of alpha5 GABA(A) receptor function or distribution, given that schizophrenia patients are known to exhibit a PPI deficit. Our data further highlight that the potential use of alpha5-selective inverse agonists to treat hippocampal-related mnemonic dysfunction needs to be considered against the possibility that such compounds may be adversely associated with deficient sensorimotor gating.

Dopamine receptor blockade in the rat medial prefrontal cortex reduces spontaneous and amphetamine-induced activity and does not affect prepulse inhibition.

The functions and interactions of cortical and subcortical dopamine systems are of interest because alterations in these systems have been implicated in neuropsychiatric diseases, such as schizophrenia. It has been proposed that prefrontal dopamine transmission may oppose dopamine transmission in subcortical sites, such as the nucleus accumbens. Accordingly, reduced prefrontal dopamine transmission would be expected to enhance or induce behavioral effects that have been associated with stimulation of accumbal dopamine receptors. In rats, spontaneous and amphetamine-induced activity is supported by dopamine receptor stimulation in the nucleus accumbens, while prepulse inhibition (PPI) of the acoustic startle response, which is used to measure sensorimotor gating and is disrupted in schizophrenia, is reduced by increased accumbal dopamine receptor stimulation. In the present experiments, we found that bilateral infusion of the dopamine D1/D2 receptor antagonist cis-flupenthixol dihydrochloride into the medial prefrontal cortex of Wistar rats (25 microg each side) reduced spontaneous activity and completely blocked induction of hyperactivity by systemic administration of D-amphetamine sulfate (1 mg/kg), while not affecting PPI. These findings do not support an antagonism between prefrontal and accumbal dopamine in the control of behavior. Rather, our data demonstrate that prefrontal dopamine transmission may modulate some behavioral processes in a similar way to accumbal dopamine.

A differential involvement of the shell and core subterritories of the nucleus accumbens of rats in attentional processes.

The nucleus accumbens comprises of two anatomically distinct subterritories: an inner core and an outer shell region. The distinct pattern of the core and shell input and output targets suggests that these two regions may mediate different behavioral processes. Using N-methyl-D-aspartate excitotoxic lesions in either the core or shell region, we investigated whether we can dissociate functionally these two subterritories. N-Methyl-D-aspartate-lesioned, sham-lesioned and non-operated animals were tested for locomotor activity in an open field and in two behavioral paradigms known to evaluate attentional deficits, namely the pre-pulse inhibition of the acoustic startle reflex and latent inhibition, measured in a two-way active avoidance paradigm. The shell-lesioned animals showed a small but significant hyperactivity in the open field when compared to the core-lesioned and to control animals. In the pre-pulse inhibition paradigm, core-lesioned animals demonstrated reduced pre-pulse inhibition to the two high pre-pulse intensities (80 dB[A], 84 dB[A]). In the active avoidance paradigm, whereas no lesion effects were detected in the non-pre-exposed groups, clear attenuation of latent inhibition was found in the shell-lesioned rats, in comparison to both core-lesioned and control rats, due to improved avoidance performance of the shell-pre-exposed group. From these results we suggest that the two subterritories of the nucleus accumbens are differentially involved in attention-related processes: the core lesion leads to significant disruption of pre-pulse inhibition while the shell lesion leads to heightened activity and significant attenuation of latent inhibition.

Effects of psychostimulant withdrawal on latent inhibition of conditioned active avoidance and prepulse inhibition of the acoustic startle response.

RATIONALE: Chronic intermittent administration of amphetamine and cocaine can precipitate psychotic episodes in humans and produce persistent behavioral changes (i.e. increased locomotion, stereotypy) in the rat. The psychostimulant sensitization model of psychosis holds that the repeated administration of drugs such as amphetamine and cocaine induces long-lasting neuroadaptations and behavioral outcomes in animals that parallel aspects of the schizophrenic condition. OBJECTIVES: In the present study, we attempted to validate this model further by examining the effects of short-term withdrawal from repeated administration of cocaine and amphetamine on performance in two animal behavioral models of cognitive deficits found in schizophrenia: latent inhibition and prepulse inhibition. Reductions in both of these behavioral phenomena have been reported in schizophrenic patients and in acutely amphetamine-treated rats. METHODS: Animals were tested after 4 days of withdrawal from 5 days of daily systemic 20 mg/kg cocaine or 1.5 mg/kg amphetamine injections for either latent inhibition of two-way active avoidance acquisition or prepulse inhibition of an acoustic startle response. RESULTS: Our results indicate that, rather than reducing the expression of these behaviors, withdrawal from either cocaine or amphetamine enhanced the expression of latent inhibition of the active avoidance response while having no effect on prepulse inhibition of acoustic startle. CONCLUSIONS: These data indicate that although the sensitized response to amphetamine and cocaine administration may model some aspects of schizophrenic psychosis, behaviors exhibited by sensitized animals in the absence of an acute drug challenge are not consistent with models of the positive symptoms of schizophrenia.

Acute withdrawal from repeated cocaine treatment enhances latent inhibition of a conditioned fear response.

Psychostimulant-induced locomotor sensitization and disrupted latent inhibition (LI) of a classically conditioned association are two paradigms that have been widely studied as animal behavioural models of psychosis. In this study we assessed the effects of withdrawal from the repeated intermittent administration of cocaine on LI of a conditioned fear response. Animals which were either preexposed (PE) to a tone conditioned stimulus (CS) or naive to the tone (i.e. non-preexposed: NPE) subsequently experienced 10 pairings of the tone CS with footshock. Afterwards, both groups received five daily injections of cocaine (20 mg/kg, i.p.) or saline. After 3 days of withdrawal from drug treatment, animals were tested for conditioned freezing to the context of the footshock chamber, and 1 day later, for conditioned freezing to the tone CS. Cocaine-sensitized animals exhibited markedly enhanced LI compared to saline-treated animals, due to the fact that NPE-cocaine animals spent more time freezing during the tone CS than NPE-saline animals, whereas PE-cocaine animals showed a tendency toward reduced freezing compared to the saline groups. While these results suggest the presence of increased anxiety in cocaine-withdrawn NPE animals, the absence of this effect in cocaine-withdrawn PE rats indicates that cocaine withdrawal also influences the retrieval of previously learned information.

The effects of water deprivation on conditioned freezing to contextual cues and to a tone in rats.

In two experiments we used an automated system for quantifying freezing responses in rats to replicate and extend Maren et al. (Maren S, DeCola JP, Fanselow MS. Water deprivation enhances fear conditioning to contextual, but not discrete, conditional stimuli in rats. Behav Neurosci 1994;108:645-9; Maren S, DeCola JP, Swain RA, Fanselow MS, Thompson RF. Parallel augmentation of hippocampal long-term potentiation, theta rhythm and contextual fear conditioning in water deprived rats. Behav Neurosci 1994;108:44-57) who found that water deprivation in rats produced a selective enhancement in conditioning to context, as opposed to conditioning to a tone. In experiment 1 we gave water deprived and non-deprived rats either three or ten pairings of a tone and foot shock. During conditioning water deprivation decreased overall freezing only in rats that received ten pairings. On 2 subsequent days we assessed conditioned freezing (1) to the contextual cues of the conditioning chamber and (2) to the tone when presented in a distinctive, novel environment. We found, in direct contrast to Maren et al. (Maren S, DeCola JP, Fanselow MS. Water deprivation enhances fear conditioning to contextual, but not discrete, conditional stimuli in rats. Behav Neurosci 1994;108:645-9), that (a) water deprived rats did not differ from non-deprived rats in levels of conditioned contextual freezing and that (b) water deprived rats did show reduced levels of freezing to the tone stimulus. In the same experiment we found that the number of tone-shock pairings did not affect levels of conditioned contextual freezing but that rats that had received three pairings did show reduced levels of freezing to the tone stimulus compared with rats that had received ten pairings, thereby demonstrating that the behavioural procedure and analysis system that we used was appropriately sensitive to differences in conditioning. In experiment 2, therefore, we sought to replicate Maren et al. (Maren S, DeCola JP, Fanselow MS. Water deprivation enhances fear conditioning to contextual, but not discrete, conditional stimuli in rats. Behav Neurosci 1994;108:645-9) using, as far as possible, exactly the same procedural parameters. Here we found that water deprivation produced no effects on conditioned freezing to the contextual cues or to the tone. We conclude that there is sufficient reason to doubt the generality of the previously reported findings.

Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome.

Rearing rats in isolation has been shown to be a relevant paradigm for studying early life stress and understanding the genesis of depression and related affective disorders. Recent studies from our laboratory point to the relevance of studying the social isolation syndrome as a function of home caging conditions. Accordingly, the present series of experiments assessed the contribution of each condition to the expression of the prepulse inhibition of the acoustic startle, food hoarding and spontaneous locomotor activity. In addition, ex vivo neurochemical changes in the brains of isolated and grouped rats reared either in sawdust-lined or in grid-floor cages were determined by measuring dopamine and serotonin as well as their major metabolites in a "psychosis circuit" that includes mainly the hippocampus and selected hippocampal efferent pathways projecting towards the anterior cingulate and infralimbic cortices, nucleus accumbens, dorsolateral caudate nucleus, amygdala and entorhinal cortex. The results of the present study demonstrate that rearing rats in isolation (i) produces a syndrome of generalized locomotor hyperactivity; (ii) increases the startle response; (iii) impairs prepulse inhibition; (iv) tends to increase food hoarding behavior; (v) increases basal dopamine turnover in the amygdaloid complex; (vi) decreases basal dopamine turnover in the infralimbic part of the medial prefrontal cortex; and (vii) decreases basal turnover of serotonin in the nucleus accumbens. In the entorhinal cortex, dopamine neurotransmission seemed to be more sensitive to the caging conditions since a decreased basal turnover of dopamine was observed in grid-reared animals. Plasma corticosterone levels were also increased in grid-reared animals compared with rats reared in sawdust cages. Finally, isolates reared on grids showed a significant positive correlation between plasma corticosterone levels and dopamine in the left nucleus accumbens.Altogether, these results support the contention that there is a link between social isolation, attention deficit, spontaneous locomotor hyperactivity and reduced dopamine turnover in the medial prefrontal cortex. Furthermore, our data demonstrate that rearing rats in grid-floor cages represents a form of chronic mild stress associated with increased corticosterone levels, decreased basal turnover of entorhinal dopamine and increased dopamine activity in the left nucleus accumbens. Finally, a significant and selective decrease in the basal turnover of serotonin in the nucleus accumbens of isolated rats may be linked to the isolation-induced locomotor hyperactivity.

Lack of effect of an early stressful life event on sensorimotor gating in adult rats.

Hypotheses of the etiology of schizophrenia emphasize the important role of perinatal insults in predisposing individuals to the development of the disease, so that an animal model in which a discrete postnatal manipulation of the infant social environment yields schizophrenia-like behavior in adulthood would be valuable in terms of the study of the neural substrate and treatment of schizophrenia. Schizophrenics demonstrate a deficit in sensorimotor gating (prepulse inhibition), and a similar phenomenon has been described in adult rats following the administration of direct and indirect dopamine agonists. Recently it has been reported that a 24 h separation of rat pups from the mother results in a disruption of prepulse inhibition at adulthood. Here we report a study which investigated the same phenomenon but which, in contrast to the previous study, utilized unrelated subjects all derived from different dams. Maternal separation was conducted for 24 h with pups aged 4, 9 or 18 days and these subjects, together with non-separated controls, were tested at age 3 months in terms of their prepulse inhibition in the acoustic startle response paradigm. Maternal separation did not disrupt prepulse inhibition. Comparison of males and females (with a maximum of one opposite-sex sibling) demonstrated that acoustic startle response and prepulse inhibition of this response was enhanced in males relative to females. This study indicates that 24 h maternal separation does not provide a robust model for studying the effects of early environmental insults on the long-term abnormal development of sensorimotor gating.

Circadian time does not modify the prepulse inhibition response or its attenuation by apomorphine.

The present study investigated the influence of circadian time (experimental testing during the light or dark phase of the light:dark cycle) on the acoustic startle response (ASR), prepulse inhibition (PPI), and apomorphine-induced PPI deficits in Wistar rats housed under a reversed light:dark cycle (lights off at 0700 h and on at 1900 h). There was no significant difference in the startle response amplitude or PPI response of animals tested during the light phase compared with those tested during the dark phase. Similarly, the response to apomorphine (0.01-0.05 mg/kg subcutaneously) was not modulated by circadian time. Thus, under the conditions adopted in the present study, ASR, PPI, and apomorphine-induced PPI deficits remained stable across the circadian cycle. Such findings may be of importance for other investigators using the PPI paradigm to study brain plasticity mechanisms and pharmacological manipulations of apomorphine-induced PPI deficits in rats housed under normal or reversed light:dark cycle conditions.

The effects of hippocampal and fimbria-fornix lesions on prepulse inhibition.

The present experiments tested the effects of conventional (dorsal aspiration and electrolytic) and excitotoxic (N-methyl-D-aspartate [NMDA]) hippocampal lesions and fimbria-fornix (FF) transection on prepulse inhibition (PPI) of startle response and on open-field activity. Activity was increased by FF transection and by conventional but not excitotoxic hippocampal lesions; complete NMDA lesion increased amphetamine-induced activity. Whereas dorsal hippocampal aspiration lesion disrupted PPI, the phenomenon was not affected by dorsal hippocampal electrolytic lesion, partial or complete excitotoxic (NMDA) hippocampal lesions, or complete FF transection, which interrupted the cholinergic input to the hippocampus as well as the hippocampal-subicular input to the nucleus accumbens. Systemic apomorphine disrupted PPI in both FF-transected rats and their controls. It is suggested that the hippocampus is essential for PPI disruption rather than for PPI expression.

Disruption of prepulse inhibition following N-methyl-D-aspartate infusion into the ventral hippocampus is antagonized by clozapine but not by haloperidol: a possible model for the screening of atypical antipsychotics.

The present study tested the effects of the typical neuroleptic haloperidol and an atypical neuroleptic clozapine on ventral hippocampus stimulation-induced disruption of prepulse inhibition (PPI). Bilateral infusions of 0.7 microg NMDA into the ventral hippocampus disrupted PPI. The impairment of PPI following the infusion was completely normalized 24 h after the infusion. This disruption of PPI was antagonized by clozapine (5.0 mg/kg), but not by haloperidol (0.2 mg/kg). Since disruption of PPI is considered to constitute an animal model of schizophrenia that is related to the deficit of sensorimotor gating observed in schizophrenic patients, these results suggest that PPI disruption induced by intra-ventral hippocampal infusions of NMDA may serve as an animal model for the selective detection of atypical antipsychotics.

Effects of smoking status and schizotypy on latent inhibition.

Two experiments investigated the effects of smoking status and schizotypy on the ability to gate out irrelevant information as assessed in auditory and visual latent inhibition (LI), Stroop effect and negative priming. The two experiments used 10 or 30 pre-exposures for auditory LI and a long or short interstimulus interval for the Stroop task, respectively, which included negative priming and served as masking task for the visual LI. Smoking status did not affect performance on any of the tasks, except for auditory LI after 30 pre-exposures, which was enhanced. The relationship between schizotypy and cognitive performance was complex. In Experiment 1, high schizotypals had smaller visual LI and negative priming than low schizotypals, whereas in Experiment 2 the reverse was observed, namely, larger LI and negative priming in high schizotypals.

Isolation rearing-induced disruption of prepulse inhibition: further evidence for fragility of the response.

The present study investigated isolation-induced disruptions of prepulse inhibition (PPI), and effects on locomotor activity as a function of home caging condition (sawdust vs grid-floor) in the Wistar rat. Isolates reared in grid-floor cages did not show a disruption of PPI. However, when isolates were reared in sawdust cages, a PPI deficit was evident. In an open field environment, isolates demonstrated significantly increased spontaneous locomotor activity compared to their group-housed counterparts, irrespective of the caging condition employed. Grouped animals reared in grid-floor cages, however, showed reduced activity compared to grouped animals reared in sawdust cages. Although d-amphetamine treatment appeared to enhance locomotor activity selectively in isolates, particularly in those reared in grid-floor cages, this result could be explained by the existing pre-drug activity levels. With respect to PPI, not only were isolation-induced deficits in the Wistar rat difficult to detect in a variable prepulse intensity PPI procedure, but when apparent, the deficits were of a fragile nature. The findings suggest that caging condition may be a critical methodological factor in experiments investigating isolation-induced PPI deficits. Indeed, our results may indicate that rearing animals in grid-floor cages represents a form of chronic mild stress, which can interfere with normal sensorimotor gating mechanisms, in addition to other behaviours.

Sex differences in the acoustic startle response and prepulse inhibition in Wistar rats.

The prepulse inhibition paradigm (PPI) is based on the phenomenon that the acoustic startle response (ASR) to an acoustic stimulus is reduced when the stimulus is preceded by a weak prepulse. It has been shown that PPI is dramatically disrupted in patients with schizotypic disorders. Since PPI can be easily tested in animals as well as in humans it is a widely used model to investigate the neurobiological mechanisms underlying those disorders. In humans it has been demonstrated that men show increased PPI at weak prepulses relative to women. Only very few studies have investigated PPI sex differences in rats and these report negative findings. Studies are reported on here where consistent differences have been found in ASR and PPI between adult male and female Wistar rats. Compilation of data from a series of experiments demonstrates that ASR and PPI are both greater in males than in females in this rat strain, a finding which is largely in line with the human evidence. This study therefore adds weight to the argument that PPI of the ASR provides an animal model with high validity for the study of important human disorders which are characterized by sensorimotor gating deficits.

The effects of smoking on acoustic prepulse inhibition in healthy men and women.

Acoustic prepulse inhibition (PPI) refers to the reduction of the startle reflex to an intense stimulus if it is preceded by a weak stimulus. Nicotine and smoking have been reported to enhance PPI in rats and in healthy men, respectively. We studied the influence of smoking on PPI in healthy men and women, comparing non-smokers, deprived smokers, and smokers smoking during the test session after deprivation or after ad libitum smoking. Smoking during the session enhanced PPI, without affecting startle reaction or habituation over time. In addition, the effect of smoking on PPI was gender dependent. In men, ad libitum smoking enhanced PPI compared with non-smokers, while, in women, deprivation reduced PPI and smoking restored PPI to the level of non-smokers.

The disruption of prepulse inhibition by social isolation in the Wistar rat: how robust is the effect?

Postweaning isolation rearing in rats is shown to have consequences for the expression of numerous behaviors. The present studies investigated isolation-induced disruptions of the prepulse inhibition (PPI) response in the Wistar rat strain, as a function of exposure of the animals to locomotor activity testing. Further, repeated testing of PPI was investigated to examine the robustness of the isolation-induced disruptions. The results indicate that experimentally naive isolation-reared animals exhibit disruptions in the PPI response that are retained in a second test 7 days later. The disruptions obtained are shown to be consistent across all pulse frequencies examined and independent of effects on startle. Exposure to activity testing, however, either before or after the measurement of PPI, abolished the isolation-induced disruption of PPI in a subsequent test. In contrast, locomotor activity testing consistently revealed a hyperactivity response in isolation-reared animals that was not influenced by the temporal occurrence of the testing. The findings are discussed relative to the interpretation of data emerging from studies where both activity testing and PPI are performed in the same animals, and in the relation to the use of PPI in isolation-reared animals as representing a nonpharmacological animal model of schizophrenia.