Investigations into aspects of schizophrenia based on the isolation rearing paradigm in the rat

Abstract

Newer antipsychotics with improved efficacy and fewer side effects are necessary in view of the current sub-optimal management of schizophrenia, a debilitating psychiatric disorder with significant disease burden. This underpins the importance of animal models for the preclinical identification of compounds with potential antipsychotic properties. Schizophrenia is thought to be in part a neurodevelopmental disorder. Work in this thesis involved behavioural, neurochemical or molecular examination of two neurodevelopmental rat models of aspects of schizophrenia. Additionally, the antipsychotic potential of cannabidiol, a non-psychoactive constituent of the cannabis plant, was further investigated. It was shown in this thesis that isolation rearing of rats for 8 weeks from weaning at 3 weeks old had unreliable or non robust effects on prepulse inhibition (PPI). However, isolation rearing-induced hyperlocomotion appears to be a more robust and consistent outcome and may be useful for the screening of potential antipsychotic drugs dosed chronically. Isolation rearing also gave rise to synaptic, myelin and GABA-related changes, as indicated by a lower immunoreactivity of synaptophysin, synapsin I, myelin basic protein and GABABR1 receptor, and a higher immunoreactivity of 2′,3′-cyclic nucleotide 3′ phosphodiesterase in specific brain regions of isolation-reared rats relative to group-reared controls. Clozapine at a dose of 5 mg/kg partially inhibited the hyperlocomotion observed in isolation-reared rats whereas cannabidiol was ineffective. In contrast, cannabidiol disrupted PPI and elicited hyperlocomotion which are indicative of a psychotic-like symptoms inducing effect. Considering the lack of robust PPI changes in isolation-reared rats, another manipulation was added to mimic the two-hit hypothesis of schizophrenia where isolation rearing was preceded by 0.2 mg/kg MK 801 administration from postnatal days 7 to 10. Two hit rats had robust PPI disruptions that persisted with repeated testings and subchronic vehicle injections as opposed to the subtle or total lack of PPI deficits in rats that were subjected to only one manipulation. Additionally, only the two-hit rats displayed hyperlocomotion and impaired novel object recognition memory. Clozapine restored all behavioural changes in the two-hit rats whereas cannabidiol disrupted PPI in controls. Sustained behavioural alterations in the two-hit rats were accompanied by changes in the expression of genes involved in neurodevelopment, neurotransmission, neuroplasticity and regulation of behaviour as indicated by microarray analysis. To conclude, although isolation rearing of rats can produce some behavioural and neurochemical changes that have been implicated in schizophrenia, robustness and extent of the behavioural changes can be greatly improved by combination with neonatal MK 801 treatment. The resultant two-hit model may be useful as an alternative tool for the screening of potential antipsychotic activity, including via chronic dosing if desired. Observations in the present work are not in support of the previously reported antipsychotic potential of cannabidiol.