Evaluation of novel dual-hit models of 'schizophrenia-like' symptoms in the rat

Schizophrenia is a debilitating disorder comprising positive, negative and cognitive deficits with a poorly-defined neurobiological basis. Animal models with greater translational reliability and validity are essential to develop improved therapies and aid understanding of disease aetiology. This thesis utilised the well-established isolation rearing developmental disruption model of schizophrenia in the rat as the base for producing novel ‘dual-hit’ combination models of the disease, with the aim of improving disease validity and model robustness. Pharmacological insults were added to the isolation rearing model, first in the form of prenatal administration of the antimitotic agent methylazoxymethanol (MAM), and subsequently perinatal treatment with the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). The resulting ‘dual-hit’ models were assessed for behavioural and neurobiological validity to schizophrenia, and the incurred deficits challenged with the atypical antipsychotic risperidone and the putative adjunct therapy lamotrigine.\ud \ud Combination of isolation rearing and prenatal MAM on gestational day 17 did not produce more robust behavioural deficits than isolation rearing alone, but did cause marked reductions in hippocampal volume, akin to those observed in the clinic. Addition of perinatal PCP treatment on post-natal days seven, nine and eleven to the isolation rearing protocol produced more robust behavioural deficits, with limitations. Baseline hyperlocomotion in a novel arena in three cohorts was accompanied by an elevated locomotor response to acute PCP treatment, highlighting sensitization. Visual and spatial learning deficits were observed in the novel object discrimination task, whilst fear-motivated conditioning was impaired in a conditioned emotional response paradigm. Preattentional processing was also somewhat deficient in combination-treated animals in the prepulse inhibition of acoustic startle paradigm. Inconsistent deficits in visuo-spatial learning and cognitive flexibility were observed in a Morris water maze task.\ud \ud Acute treatment with the atypical antipsychotic compound risperidone at 0.5mg/kg caused marked sedation. At lower doses, pretreatment 30 mins prior to behavioural testing elevated prepulse inhibition and reversed emotional conditioning deficits, and returned baseline locomotor activity to levels similar to control. There was no effect on visual reference memory deficits. Conversely, pretreatment with the sodium-channel blocker lamotrigine reversed a deficit in visual reference memory, but had no effect on sensorimotor gating or fear-motivated conditioning.\ud \ud These data suggest that the combination of isolation rearing and perinatal PCP treatment to rats produces a model of schizophrenia-like symptoms that possesses some validity to the human condition, but lacks the desired robustness of a preclinical model. Further validation and improvement may allow this model to become a useful tool in on-going preclinical research