The two-hit hypothesis of schizophrenia proposes that the development of the illness involves an early neurodevelopmental stress component which increases vulnerability to later stressful life events, in combination leading to overt disease. This thesis describes a two-hit animal model, comprising of an early first hit in the form of 24 hours maternal deprivation on postnatal day 9, and a late second hit simulated by 2 weeks of corticosterone administration from 8 to 10 weeks of age in rats. The project included behavioural studies on prepulse inhibition (PPI) regulation, locomotor activity, and learning and memory, and neurochemical and molecular studies on dopaminergic parameters, brain-derived neurotrophic factor (BDNF) and glucocorticoid receptor (GR) expression. / In the two-hit animals, there was little effect on baseline PPI or locomotor activity. However, the effect of acute treatment with the dopaminergic stimulants, apomorphine, amphetamine and quinpirole, was markedly diminished. There were differential effects of either maternal deprivation or corticosterone administration on the action of these drugs. However, there was no change in any of the groups in the effect of the serotonin-1A receptor agonist, 8-OH-DPAT, on PPI, or the effect of amphetamine and phencyclidine on locomotor activity. (For complete abstract open document)

Prepulse inhibition (PPI) is an operational measure of sensorimotor gating and is known to be reduced when the dopamine D2 receptor is activated. We used a rodent model of psychosis in which increases in dopamine D2 receptor sensitivity are produced through neonatal quinpirole (a dopamine D2 / D3 agonist) treatment to rats. Rats were administered quinpirole (1mg/kg) or saline from postnatal day (P) 1-21. Rats were raised to adulthood and tested on PPI. Results showed that neonatal quinpirole treatment produced a significant reduction in PPI, and nicotine exacerbated this reduction. This reduction was partially blocked by the nicotinic antagonist mecamylamine. Brain tissue was analyzed for regulators of G-protein signaling (RGS) and results showed that neonatal quinpirole significantly decreased RGS9, but increased RGS17 as compared to controls. These results appear to indicate that the G-protein couples more efficiently to the D2 receptor, and nicotine exacerbates PPI deficits in D2 receptor-primed rats.