A series of experiments examined the effect of the adenosine receptor agonists N(6)-cyclohexyladenosine (CHA), N(6)-phenylisopropyladenosine (R-PIA) and 5'-N-ethylcarboxamidoadenosine (NECA); the adenosine receptor antagonists theophylline, caffeine and 8-phenyltheophylline (8-PT), and the adenosine uptake inhibitor dipyridamole on acquisition of a single trial passive avoidance learning by mice. The adenosine receptor agonists CHA (0.05, 0.1, 0.2 and 0.4 mg/kg) and R-PIA (0.00625, 0.125, 0.25 and 0.5 mg/kg) administered 1 h before the training session decreased retention dose dependently while the other adenosine receptor agonist NECA (0.0025, 0.005 and 0.01 mg/kg) had no effect. The response induced by the adenosine receptor agonists CHA and R-PIA was attenuated by the pretreatment of animals with low doses of the adenosine receptor antagonists 8-PT (2.0 mg/kg) and theophylline (25 mg/kg) but not with higher doses of the antagonists. The higher doses of the antagonists decreased the passive avoidance. Dipyridamole (7.5, 15, 30, 60 and 120 mg/kg) showed no significant effect. It is concluded that adenosine A1 receptor activation decreases the acquisition of a passive avoidance response.