Intracerebroventricular (i.c.v.) administration of ouabain has been shown to alter motor activity in the rat. It has been purported that this may model the behavioral abnormalities of human manic-depressive (bipolar) illness. Since manic-depression is a recurrent condition, we elected to investigate the effects of the multiple administration of i.c.v. ouabain. Male Sprague-Dawley rats were allowed to acclimate to the animal facility for 7-10 days after which time i.c.v. cannulae were placed. Animals received two i.c.v. injections of either ouabain (10[-3] M) or artificial cerebrospinal fluid (aCSF) 9 days apart, so that 6 rats received aCSF-aCSF, 6 received ouabain-aCSF, and 6 received ouabain-ouabain. Behavioral activity was evaluated in an open field (86 x 86 cm subdivided into sixteen 21.5 x 21.5-cm squares) for 20 min at baseline and immediately following each i.c.v. injection. After the last behavioral test, the animals were killed, and the brains were rapidly harvested and dissected over ice. Specific ouabain binding and sodium pump activity were determined. A single dose of ouabain produced a marked increase (297.0%, p = 0.002) in open field activity compared to both baseline behavior and to aCSF injected animals. The effects of ouabain appeared to last for 9 days. A second i.c.v. injection of either ouabain (136.5 +/- 60.4 SEM) or aCSF (108.0%, p < 0.01) had no effect on the activity level which was intermediate between the initial ouabain hyperactivity and the baseline level. Nine days after ouabain administration, hippocampal ouabain binding was increased relative to the control group (5477 +/- 485.7 vs. 3579 +/- 518.6, p < 0.05) and sodium pump activity was relatively lower (2293.8 +/- 265.5 vs. 3174.2 +/- 410.5, p < 0.05).