RATIONALE: 5-HT(6) receptors are predominantly located in the brain and may be involved in cognitive processes. The aim of this study was to assess the effects of two potent and selective 5-HT(6) receptor antagonists, SB-271046-A and SB-357134-A, on learning and memory in the rat. METHODS: Spatial learning and memory was assessed by testing the effects of SB-271046-A and SB-357134-A on acquisition and retention of a water maze task. RESULTS: In the water maze, administration of SB-271046-A or SB-357134-A (3 or 10 mg/kg) had no effect on learning per se. At 10 mg/kg, however, both compounds produced a significant improvement in retention of a previously learned platform position when tested 7 days after training. By contrast, the acetylcholinesterase inhibitor, Aricept (donepezil, 0.1, 0.3 mg/kg PO) had no effect in this task. CONCLUSIONS: This study demonstrates that systemic administration of SB-271046-A and SB-357134-A produces improvements in retention of a water maze task in the rat. These data indicate that 5-HT(6) receptor antagonism may be involved in cognitive function.