The overall purpose of this study was to investigate the effects of chronic treatment, with therapeutically relevant doses, of memantine on two forms of synaptic plasticity in the rat hippocampal formation in vivo: first, on the induction of long-term potentiation (LTP) in a region of hippocampus rich in NMDA receptors (i.e. the fascia dentata), and second, on the behavior-induced form of plasticity that we have called short-term exploratory modulation (STEM). Data showed that semichronic treatment of rats with memantine at 30 mg/kg/day p.0. resulted in peak serum levels of 5 uM 5 h after administration, and is likely to have resulted in peak CSF levels of -2.5 uM. The average serum concentration over 24 h of 2.5 pM was 4-5 times higher than that measured in the serum of demented patients under semi-steady-state memantine therapy. In addition, chronic treatment of adult male F-344 rats (9-1 2 months old) with therapeutically relevant doses of memantine (30 mg/kg/day in chow for >8 weeks) increased the maintenance of long-term potentiation of field excitatory postsynaptic potentials from perforant path-granule cell hippocampal synapses. In contrast, there was no effect of memantine on exploratory behavior or the amount of STEM observed. These studies provided the first electrophysiological evidence that memantine can increase the durability of synaptic plasticity and provided preclinical confirmation of the cognitive improvement seen with memantine in the treatment of demented patients.