The present study investigates the effects of concurrent manipulations of nicotinic cholinergic receptors (nicotinic cholinergic agonist: nicotine 0.03, 0.1, 0.3 mg/kg, nicotinic cholinergic antagonist: mecamylamine 7.5 mg/kg) and serotonin neurons (p-chlorophenylalanine (PCPA), 400/kg mg on each of 3 days) on spatial navigation (water maze, WM) and passive avoidance (PA) performance. Nicotine did not affect PA performance but at the highest dose slightly impaired WM performance. PCPA did not affect WM navigation or PA performance in saline or nicotine-treated rats. Nicotine restored WM and PA performance defect in mecamylamine pretreated rats. PCPA aggravated the WM defect and decreased the WM performance-improving effect of nicotine in mecamylamine pretreated rats. PCPA did not aggravate the PA performance defect of mecamylamine but completely blocked the PA performance-improving effect of nicotine in mecamylamine pretreated rats. These results suggest that serotonergic and nicotinergic cholinergic systems jointly modulate performance in WM and PA tests.