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Memantine, a selective antagonist of the N-methyl-D-aspartate receptor, is approved for the treatment of moderate to severe Alzheimer's disease. Ion dysregulation is thought to be involved in the pathophysiology of bipolar illness, suggesting that memantine may be effective in treating bipolar manic and/or depressive episodes. We utilized two preclinical models of mania that mimic pathophysiologic changes seen in bipolar illness to examine the potential efficacy of memantine in the treatment of this disorder. Locomotor hyperactivity of male Sprague-Dawley rats in an open field was induced with intracerebroventricular (ICV) administration of 10(-3) M ouabain. Memantine (2.5, 5 or 7.5mg/kg), lithium (6.75 mEq/kg), or vehicle were administered acutely via intraperitoneal injection immediately prior to ouabain, then chronically for 7 days (oral memantine 20, 30, and 40 mg/kg/day in water; lithium 2.4 g/kg food). In a second model of bipolar disorder, cycling between population spikes and epileptiform bursts was investigated in rat hippocampal slices treated with ouabain (3.3 μM) alone or in combination with memantine (0.5, 1.0, and 5.0 μM). Ouabain-induced hyperlocomotion was normalized with acute and chronic lithium and chronic use of memantine. Memantine delayed the onset of ouabain-induced-cycling in hippocampal slices. Memantine may have antimanic properties.