The effects of repeated administration of the selective adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), the selective adenosine A2 receptor agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA), the non-selective adenosine A1/A2 receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3 dipropylxanthine (DPCPX) and the selective adenosine A2 receptor antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-(4,3-e)1,2,4-triazolo(1,5 -c)pyrimidine (SCH 58261) on the anticonvulsant activity of 3-(2-carboxypiperazine-4y)propenyl-1-phosphonic acid (CPPene), a selective N-methyl-D-aspartate receptor antagonist, were evaluated in audiogenic sensible dilute brown agouti mice DBA/2J (DBA/2). Mice were treated intraperitoneally twice daily for 7 days with CCPA 0.11 mg/kg, 2HE-NECA 0.056 mg/kg, NECA 0.11 mg/kg, DPCPX 0.5 mg/kg and SCH 58261 0.5 mg/kg followed by 2 vehicle injections (the wash-out period of 1 day) and subsequently CPPene was administered intracerebroventricularly. Audiogenic seizures were delivered 30 min after CPPene administration. Repeated treatment with CCPA significantly reduced the anticonvulsant properties of CPPene against audiogenic seizures. A weak and not significant reduction of anticonvulsant effects of CPPene was observed following repeated administration of NECA, whilst the repeated administration of 2HE-NECA did not decrease the antiseizure activity of CPPene. Conversely, repeated administration of DPCPX markedly potentiated the anticonvulsant properties of CPPene, whilst the repeated treatment with SCH 58261 did not increase the anticonvulsant activity of CPPene. The present results indicate that repeated treatment with CPPA, a selective adenosine A1 receptor agonist, decreases the anticonvulsant properties of CPPene, whilst the repeated administration of DPCPX, a selective adenosine A1 receptor antagonist, potentiates the anticonvulsant effects of CPPene. The compounds acting as selective agonists or antagonists of adenosine A2 receptors do not affect the antiseizure activity of CPPene. In conclusion, the repeated interaction of agonists or antagonists with adenosine A1 receptors seems to induce changes on anticonvulsant activity of CPPene, whereas drugs acting at adenosine A2 receptors do not.