Adenosine A2A receptor antagonists alleviate memory deficits caused by aging or by administration of beta-amyloid peptides in rodents, which is in accordance with the beneficial effects of caffeine consumption (an adenosine receptor antagonist) on memory performance in aged individuals and in preventing Alzheimer's disease. We now tested if A2A receptor blockade affords a general beneficial effect in different experimental paradigms disturbing memory performance in rodents. The beta-amyloid fragment present in patients with Alzheimer's disease (Abeta1-42, 2 nmol, icv) decreased spontaneous alternation in the Y-maze after 15 days (29%) to an extent similar to the decrease of memory performance caused by scopolamine (2 mg/kg, ip) or MK-801 (0.25 mg/kg, ip) after 30 min (28% and 39%, respectively). The selective A2A receptor antagonist SCH58261 (0.05 mg/kg, ip every 24 h, starting 30 min before the noxious stimuli) prevented Abeta1-42-induced amnesia, but failed to modify scopolamine- or MK-801-induced amnesia. Similar conclusions were reached when testing another A2A receptor antagonist (KW6002, 3 mg/kg, ip). These results indicate that A2A receptors do not affect general processes of memory impairment but instead play a crucial role restricted to neurodegenerative conditions involving an insidious synaptic deterioration leading to memory dysfunction.