The overarching aim of this report was to determine the effect of sub chronic oral administration of memantine on hippocampus-based spatial learning and other general behaviors in the APPswe/ PS1 transgenic mouse model of AD. Eight-month-old male transgenic mice, and their nontransgenic (NT) litter mates were orally administered a dose of memantine yielding therapeutic plasma concentrations of the drug and mimicking its clinical use. At this age, APP/PS1 mice show elevated levels of β-amyloid peptides in several brain regions. APP/PS1 mice exhibited less exploratory rearing and increased aggressive behavior compared with NT mice. In the water maze test for spatial learning, APP/PS1 mice had longer escape latencies to both hidden and visible platforms, but they did not differ from NT mice in their swimming speed. Memantine significantly improved the acquisition of the water maze in transgenic mice (but not NT mice) without affecting swimming speed. Memantine did not affect either locomotor activity or aggressive behavior in either transgenic or NT mice. These data indicate that memantine improves hippocampus-based spatial learning in a transgenic mouse model of AD without producing nonspecific effects on locomotion/exploratory activity.