Background: Ketamine is an NMDA receptor antagonist shown to produce deficits in humans on cognitive battery of tasks involving attention and memory. Previous work in our laboratory using the odour span task (OST) has shown nicotine to be effective in enhancing cognitive performance in normal animals. The aim of this study was to develop a rodent model of cognitive deficits using ketamine exposure in the OST to evaluate the ability of nicotine to restore performance. Methods: Rats were trained in a non-matching to sample rule, then the full OST, which involved identifying a novel odour from an increasing number of presented odours. Male hooded Lister rats were performance matched and randomly allocated to three treatment groups (n=8). Animals were sub-chronically exposed to ketamine daily (10, 30mg/kg i.p. or vehicle) for 5 consecutive days after reaching a baseline level of performance. Ketamine produced a dose-dependent impairment that was stable over 14days. Animals were therefore tested with acute doses of nicotine (0.025, 0.05 and 0.1mg/kg) and saline in a randomised sequence. Results: Nicotine doses in 0.1 and 0.5mg/kg were effective in restoring performance to baseline levels in both ketamine-treated groups. Similar levels of improvement with nicotine were evident in control subjects, with the most significant effect observed following 0.05mg/kg nicotine. Discussion: These data suggest that ketamine in the OST may be useful in examining novel treatments to restore cognitive impairments associated with neuropsychiatric disorders such as schizophrenia, and adds to the evidence suggesting that neuronal nicotinic receptors may be viable targets for intervention. Further behavioural work but also in-vitro electrophysiology will be undertaken to elucidate the role of specific receptors involved this process.