Behavioural abnormalities and novel pharmaceutical intervention in acute and developmental rat models of psychiatric illness

Abstract

This thesis explores various methods of modelling psychiatric illness in rats. I used two distinct pharmacological manipulations to induce acute states that resemble psychosis, as well as a prenatal manipulation via maternal inflammation to produce a neurodevelopmental model. I assessed the effects of these manipulations in a variety of behaviour tasks relevant to psychiatric illness. The first experiment (Chapter 2) uses a prepulse inhibition (PPI) behaviour test to demonstrate the effects of two enantiomers of putative antipsychotic GOV on APO or MK-801 disrupted sensorimotor gating. The use of APO and MK-801 allow acute manipulation of DAergic and glutamatergic systems, respectively; the two neurotransmitter systems implicated in the main theories explaining schizophrenia pathology. The l-, but not d- enantiomer of GOV was effective in restoring PPI, and effect which may be due to l-GOV’s dual effects of D2 receptor antagonism and increased prefrontal cortex (PFC) DA efflux while the d- enantiomer lacks a strong D2 antagonistic effect. These results support previous findings that l-GOV may have potential for use as an antipsychotic. The second set of experiments are presented in Chapters 3 and 4 and use a neurodevelopmental model of maternal immune activation (MIA) during pregnancy. Pregnant dams are treated with a single intravenous injection of immune stimulant polyinosinic:polycytidylic acid (polyI:C) or saline on gestational day (GD) 15. In the acute phase following treatment (48 h), dams that received polyI:C displayed significantly lower body weight compared to controls and maternal serum collected 3 h post treatment contained elevated levels of immune cytokines IL-6 and CXCL1 as determined by ELISA. When the offspring were delivered, pups born to polyI:C-exposed dams were significantly smaller than control pups. Long-term follow-up of the adult male offspring in Chapter 3 show the polyI:C offspring display a psychiatric-like phenotype characterized by behaviour abnormalities related to the positive, negative and cognitive symptoms of schizophrenia. In particular, male polyI:C offspring were more sensitive to the locomotor-inducing effects of systemic MK-801 and had deficient social interaction behaviour compared to controls. Male polyI:C offspring were selectively impaired at visual and crossmodal memory, as well as oddity preference. Two operant tasks were also used to asses cognition in the male offspring. Operant set-shifting and reversal learning used lever-equipped operant chambers to assess cognitive flexibility and found a selective facilitation in set shifting performance with no effect on initial visual cue learning or reversal learning. Testing with a touchscreen-based reversal learning task also showed no effect on initial cue learning but polyI:C offspring were impaired at reversal learning, specifically in the late phase. The effects of MIA on the behaviour profile of the adult female offspring is highlighted in Chapter 4. The females were tested in the same behaviour battery as their male siblings, with the exception of the operant tasks. Female offspring displayed a similar schizophrenia-like behavior profile, including reduced social interaction, and impaired visual recognition memory. Females failed to show a group difference in locomotor response to MK-801 at the dose examined, and neither group could perform the crossmodal memory task. When the male and female results were analysed together in a sex by treatment design, no significant evidence for sex differences were found. In addition to the behaviour effects seen in MIA offspring, we were interested in the possibility of a relationship between maternal serum cytokine levels and the severity of the behavioural abnormalities in the offspring. Bivariate correlations were conducted on these data, but no robust relationships were observed, suggesting that IL-6, TNF-, and CXCL1 concentrations 3 h post polyI:C injection are not good indicators of later behaviour effects. This thesis uses these 3 data chapters to highlight concepts of validity in preclinical research, and the challenges of modelling complex human psychiatric conditions in rats while comparing and contrasting the models used. Overall, a researcher’s choice of model depends on many factors, yet both pharmacological and neurodevelopmental approaches achieve sufficient levels of validity to advance the understanding of psychiatric illness for the eventual goal of improved disease management.