WE investigated the effect of nicotine, a nicotinic agonist, and D-cycloserine (DCS, a partial glycine-B agonist of the N-methyl-D-aspartate (NMDA) receptor complex) on aging-induced defects of water maze (WM) spatial navigation in rats. Nicotine (0.3 mg kg−1, s.c.) or DCS (10 mg kg−1, i.p.) enhanced acquisition of the WM task. A combination of subthreshold doses of nicotine (0.1 mg kg−1) and DCS (3 mg kg−1) improved WM acquisition. A subthreshold dose of a competitive NMDA antagonist, CPP (1 mg kg−1), blocked the effect of nicotine (0.3 mg kg−1) on WM acquisition. A nicotine antagonist, mecamylamine (10 mg kg−1), impaired WM acquisition and had no effect on retention, but did not block the effect of DCS 10 mg kg−1. The results suggest that nicotine and DCS synergistically enhance spatial navigation in aged rats.