|dc.description.abstract||PURPOSE: Psychotic (positive) symptoms are the most distinctive feature of schizophrenia, although negative symptoms such as emotional flattening, social withdrawal and cognitive disturbances are the most treatment resistant manifestation of the illness. Schizophrenia is a progressive degenerative illness that has been causally linked to environmental and neurodevelopmental factors, as well as dysfunctional redox balance. Validated animal models are useful in identifying and studying novel neurobiological targets for neuropsychiatric illnesses. Post weaning social isolation rearing (SIR) in rats has been proposed to model the neurodevelopmental aspects of schizophrenia. We validated the SIR model with respect to effects on sensorimotor gating and social interaction, deficits of which are core symptoms of schizophrenia. Following this, effects on the levels of oxidative stress were determined in the frontal cortex and striatum of rats exposed to SIR, two brain regions strongly implicated in the pathology of schizophrenia. Finally, in order to more closely relate these bio-behavioural changes to the human condition, we studied the overall effect of sub-chronic treatment with the atypical antipsychotic, clozapine, on the above described behavioural and neurochemical parameters.
METHODS: Male Sprague-Dawley (SD) rats (10 rats/group) were used. In a non-treatment arm, four groups of rats were randomly separated at weaning and exposed to either 8 weeks SIR or 8 weeks social rearing. At the respective time point of 8 weeks two groups were subjected to behavioural testing of mean startle amplitude (at 120dB) and percentage prepulse inhibition (%PPI) of the acoustic startle (AS) reflex (at 72, 76, 80 and 86dB prepulse), and various social interactive and self-directed behaviours were accessed using the open field test (OFT). The remaining two groups were sacrificed at 8 weeks and brain tissue was harvested for analysis of superoxide dismutase activity, oxidized (GSSG) versus reduced (GSH) glutathione ratio, and levels of lipid peroxidation, in the frontal cortex and striatum. In the treatment arm, consisting out of eight groups of animals, four groups of SIR rats received either saline or clozapine (5mg/kg i.p.) for the last 11 days of SIR. The remaining four groups were socially reared and also received either saline or clozapine treatment as above. At 8 weeks, four groups were subjected to behavioural testing as described above and a parallel neurochemical study was performed using the same layout as above, except that after the 8 weeks, neurochemical redox analysis were done as described above. Mixed statistical modelling with repeated measures and appropriate post hoc tests were used to access the effects of SIR with and without treatment on PPI and mean startle. Social interaction in SIR and socially reared animals, with and without treatment, was analyzed using 1-way ANOVA with suitable post hoc testing. Mixed linear models with repeated measures and appropriate post hoc tests were used for analysis of the redox data in SIR and socially reared animals, with and without treatment.
RESULTS: In the non-treatment arm, %PPI was significantly reduced in SIR versus socially reared rats. Deficits in various social interactive behaviours were observed in SIR versus group-housed rats, as well as increased locomotor activity and self-grooming. Superoxide dismutase activity and oxidized versus reduced glutathione ratio were significantly decreased, together with a significant increase in products of lipid peroxidation, in isolation reared versus socially reared rats.
Following clozapine treatment, %PPI in isolates was significantly elevated by clozapine versus saline treatment (i.e. reversed the effect of SIR). %PPI was unaltered in socially reared animals receiving either treatment. As with the non-treatment group, social interactive behaviours were significantly impaired in isolates receiving saline, while locomotor activity and self-grooming were increased. SIR rats receiving only saline showed similar altered redox state as the non-treatment groups, while clozapine treatment effectively reversed deficits in %PPI, aberrant social behaviours and redox alterations in the SIR rats, with limited to no effects in the socially reared controls.
CONCLUSION: SIR thus significantly disrupts sensorimotor gating and social behaviours in male Sprague-Dawley rats, while at the same time evokes a significant disruption of redox state in both the frontal cortex and striatum of these animals, with distinct evidence for increased oxidative stress in these brain regions. Importantly, both altered behaviour and redox state are reversed by sub-chronic clozapine treatment. SIR is therefore a useful, non-lesion and non-pharmacological neurodevelopmental animal model of schizophrenia that presents with robust face, predictive and possibly construct validity for schizophrenia.||