Transition metals have been associated with impaired neurological development, and neurobehavioral activity. Metallothioneins are central components in the metabolism and detoxification of a variety of metals, however, little is known concerning their role in cognitive function. To determine the role of metallothionein in learning and memory, mice with deletions of two metallothionein genes (MT-1 and MT-2) were trained on a win-shift task in an 8-arm radial maze. The parental strain of mice learned the maze at a normal rate over an 18-session acquisition period. In contrast, the MT-1/MT-2-null mice, which had a similar choice accuracy level at the beginning of training, showed a poorer rate of learning during the training period. In addition, the MT-1/MT-2-null mice showed significantly less choice accuracy than the parental strain. The MT-1/MT-2-null mice also showed a significant hypoactivity during the early and middle parts of acquisition training, but they were not different from the wildtype controls during the final phase of training. Nicotine treatment, which can improve working memory, eliminated the impairment associated with the deletion of the MT-1 and MT-2 genes in a dose-related fashion after acquisition training in the aging adult mice. These results suggest that metallothioneins, through there roles in metal physiology or cellular protection, are involved in spatial learning and memory function.