This study was undertaken to verify the effects of chronic stress and lithium treatments on the hippocampal Na +,K +-ATPase activity of rats, as well as to investigate the effects of stress interruption and post-stress lithium treatment on this enzyme activity and on spatial memory. Two experiments were carried out; in the first experiment, adult male Wistar rats were divided into two groups: control and submitted to a chronic variate stress paradigm, and subdivided into treated or not with LiCl. After 40 days of treatment, rats were killed, and Na +,K +-ATPase activity was determined. In the second experiment, rats were stressed during 40 days, and their performance was evaluated in the Water Maze task. The stressed group was then subdivided into four groups, with continued or interrupted stress treatment and treated or not with lithium for 30 additional days. After a second evaluation of performance in the Water Maze, rats were killed and Na +,K +-ATPase activity was also measured. Results showed an impairment in Na +,K +-ATPase activity and in Water Maze performance of chronically stressed rats, which were prevented by lithium treatment and reversed by lithium treatment and by stress interruption. These results suggest that the modulation of Na +,K +-ATPase activity may be one of the mechanisms of action of lithium in the treatment of mood disorders.