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. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2010.

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. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2010.

Tryptophan depletion is a non-pharmacological and non-invasive method extensively used to investigate the role of serotonin (5-hydroxytryptamine in humans and animals. The method is based on reducing the availability of the essential amino acid tryptophan, the dietary serotonin precursor. As a precursor of serotonin, L-Tryptophan has a key role in the regulation of many physiological processes and, inter alia, in the pathology and pathophysiology of neuropsychiatric disorders and diseases. Despite the fact, that the method of tryptophan depletion has been applied in many experimental studies, the exact mechanism, by which tryptophan depletion inducted neurophysiological effects, remain unclear. Also, the protentional use of this method together with other drug coadministration has not been explored in detail yet. In this thesis, the most possible mechanisms of tryptophan depletion are discussed. Biochemical and behavioural effects of low dose of dizocilpine (0.1 mg/kg and 0.15 mg/kg) in animal model of tryptophan depletion are investigated as well. And finally, effects of administration of allopregnanolone and tacrine in model of tryptophan depletion with coadministration of MK-801 are studied. The results show that acute tryptophan depletion with prior starvation, not chronic depletion, caused...

Background: The main aim of the studies in this thesis is to provide insights into the neonatal phencyclidine (PCP) induced deficits in male and female rats as a neurodevelopmental animal model of schizophrenia. Methods: Both male and female rats were treated with neonatal PCP on postnatal days (PNDs) 7,9 and 11 or vehicle, followed by weaning on PND 21-22. The rats were then tested in behavioural paradigms such as novel object recognition, spatial memory and social interaction in their adolescent and adult stages and were also tested with acute treatment of typical and atypical antipsychotic agents. Results: Neonatal PCP treatment (10 & 20 mg/kg in males and 10 mg/kg in females; once a day for 3 days on PND 7,9 and 11) caused novel object recognition and spatial memory impairment in male and female rats both in the adolescent (PND35-56) and in the adult stages (PND>56) (chapter 2) and robust deficits in social interaction behaviours in the adolescent stage. The SI deficits were observed in adulthood in female but not in male rats thereby establishing a sex-specific social behavioural deficit (chapter 3). The object memory and social interaction deficits induced by neonatal PCP treatment were reversed following acute risperidone but not haloperidol. Finally, the temporal profile of this treatment regime was investigated and the male and female animals were tested on PND 190 and PND 365. The animals did not have any challenge dose of PCP during their testing stage. The result showed that there was significant deficit in object and spatial recognition memory in both male and female animals at both time points, thereby establishing enduring deficits. Conclusion: Given the heterogeneity of the schizophrenic disorder and its complex aetiology, it is understandably difficult to find animal models that completely mimic most or all of the symptoms associated with the disorder. However, data from the studies in this thesis support the use of neonatal PCP as a valid animal model of cognitive and negative symptoms, and explores the effect of antipsychotics in understanding the model. Also, in light of the efficacy of neonatal PCP to produce robust object, spatial memory and social interaction deficits in rats, it appears that this model may be a useful tool to investigate the potential of novel therapeutic candidates that may help improve therapy and understand the illness.