Both nicotinic cholinergic and NMDA glutaminergic systems are important for memory function. Nicotine has been found repeatedly to significantly improve working memory performance in the radial-arm maze. The NMDA antagonist dizocilpine has been found to impair working memory performance. There is neuropharmacological evidence that these two systems are functionally related. Nicotine is potent at releasing many transmitters including glutamate. The current study was conducted to examine the interaction of nicotinic and NMDA systems with regard to working and reference memory. Rats were trained on a working/reference procedure on a 16-arm radial maze. After acquisition, they were administered nicotine (0, 0.2, and 0.4 mg/kg) and dizocilpine (0, 100, and 200 microg/kg) alone or in combination in a repeated measures, counterbalanced design. As seen previously, nicotine at a dose of 0.2 mg/kg caused a significant improvement in working but not reference memory performance in the radial-arm maze. The 200 microg/kg dose of dizocilpine made the rats nonresponsive on the maze so that choice accuracy could not be assessed. The 100 microg/kg dose of dizocilpine caused significant impairments in both working and reference memory. The 0.4 mg/kg dose of nicotine significantly attenuated the dizocilpine-induced deficit in both working and reference memory. NMDA blockade impairs working and reference memory and blocks the expression of the working memory improvement caused by 0.2 mg/kg of nicotine. However, a higher dose of 0.4 mg/kg of nicotine is effective at attenuating the dizocilpine-induced deficit, even though this dose alone is not effective in improving performance. A second study examined the effects of a lower dose range of dizocilpine. Comensurately smaller memory impairments were seen with lower doses of dizocilpine down to 12.5 microg/kg, which did not produce any significant effects on memory performance or response latency. Nicotine had a more modest effect in attenuating the smaller deficits caused by these lower doses of dizocilpine. These studies provide evidence for important interactions between nicotinic and NMDA systems with regard to memory function.