Behavioural, pharmacological and neurochemical studies of social isolation rearing in rats
Toua, Carl Christiaan
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Purpose: Schizophrenia affects approximately 1% of the population. Despite marked improvement in drug treatment, 20% of patients remain treatment resistant while motor side effects hamper compliance and outcome. A better understanding of the disorder is needed, as is the need for new and improved drug treatment. Due to shown correlation between animal models to human counterparts, validated animal models enable screening and details study of the neurobiological underpinnings and treatment of a psychiatric illness. Adverse life experiences during early development have been advocated as an important risk factor in the development of schizophrenia. The neurodevelopmental theory of schizophrenia suggests a dysfunction in glutamate, particularly in the frontal cortex, where it impacts on brain development and function. Deficits in sensory motor gating, such as altered prepulse inhibition (PPI) of startle, are a typical manifestation of schizophrenia. The aim of this study was firstly, to study PPI changes in rats following acute challenge with the glutamate NMDA antagonist, dizocilpine (MK-801), and its dose-dependent reversal by atypical and typical neuroleptics. Thereafter, we sought to determine the relationship between PPI changes and frontal cortical NMDA and D-i receptor binding characteristics in a neurodevelopmental anima! model of schizophrenia, based on the concept of isolation rearing, and its subsequent response to sub-chronic treatment with atypical and typical antipsychotics. Methods: PPI testing: PPI was determined using a San Diego SR-lab startle response system. 120 dB pulses were presented with or without prepulses (76 dB, 80 dB, 84 dB), using a 67 dB background noise. MK-801 model: Animals received either saline (i.p.) pre-treatment 30 min prior to PPI testing, followed by either a second saline injection (control), or MK-801 (0,25 mg/kg i.p.) 15 min prior to PPI testing. Further groups were pre-treated with increasing dosages of either clozapine (5 or 10 mg/kg i.p.) or haloperidol (0,1; 0,2 or 0,5 mg/kg i.p.) 30 min before PPI, followed 15 min later by either saline or 0,25 mg/kg MK-801. Catalepsy: Catalepsy was routinely assessed using a rat catalepsy box, repeated at 30 min intervals for 240 min after neuroleptic administration. Social isolation model: Animals were group- or isolation-housed for 8 weeks and assessed for deficits in PPI, as well as effects on frontal cortical NMDA and Di receptor binding characteristics. Isolation groups were injected with either clozapine, haloperidol or saline in the last 11 days of isolation rearing, using dosages identified in the aforegoing Mk-801 study, and their effects on PPI and cortical receptor binding determined. In addition, the effect of 4 weeks re-socialisation during the last 4 weeks of the isolation period, and its effects on PPI, was studied. Additional validation studies were performed on NMDA receptor binding in the nucleus accumbens in isolation reared rats with and without chronic drug treatments. In order to verify the effects of injection stress on PPI and to exclude it as a possible confounding factor in the chronic drug treatment studies, we studied the effect of handling in group-housed and isolation reared rats and the resulting effects on PPI. Results: MK-801 evoked significant deficits in PPI that were reversed by 5 mg/kg and 10 mg/kg clozapine but not by dosages of haloperidol that did not simultaneously induce catalepsy (0,1; 0,2 mg/kg). Significant deficits in PPI, together with increased frontal cortical NMDA density (with a decrease in affinity), and decreased D$_1$ receptor density (and increased affinity), were induced after 8 weeks of social isolation. The associated PPI deficits induced by social isolation stress (SIS) could not be reversed by re-socialization. NMDA receptor binding characteristics in the nucleus accumbens were not altered in the social isolation paradigm. Chronic clozapine but not haloperidol treatment blocked PPI deficits following social isolation, with haloperidol not affecting NMDA receptor density, but clozapine significantly increasing this compared to the isolation-reared animals. While clozapine did not alter Di receptor density compared to the isolated animals, haloperidol significantly reduced this. In both treatment groups cortical NMDA receptor affinity was, however, significantly increased compared to that of the isolation reared animals, with Di receptor affinity also increased by haloperidol and a tendency of increased Di receptor affinity was shown by clozapine in isolation reared animals. No changes were observed in the nucleus accumbens with respect to NMDA receptor binding characteristics. Conclusion: Rodents reared in isolation have significant deficits in sensory motor gating that are correlated with up-regulation of frontal cortex NMDA receptors and down-regulation of Di receptors. Moreover, chronic treatment with clozapine but not haloperidol reverses SIS induced PPI deficits, similar to that observed during hypoglutamatergia induced in the acute MK-801 model, confirming that PPI deficits evoked by either pharmacological means or by neurodevelopmental trauma represent glutamate driven mechanisms that respond selectively to atypical antipsychotic agents. Haloperidol abrogates cortical D-i receptor density in animals subjected to isolation stress, while clozapine is conservative in this action. The atypical action of clozapine involves bolstering of glutamatergic pathways, while striving to maintain cortical dopaminergic transmission.
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