BACKGROUND Learning and memory processes can be affected by morphine administration. It has been previously demonstrated that the effects of morphine depend on the timing of drug administration. In the present study, the effects of microinjections of a NMDA receptor agonist and antagonist into the CA1 regions of the dorsal hippocampi (intra-CA1) on repeated pretreatment of morphine-induced prevention of morphine-induced amnesia have been investigated. METHODS Step-through inhibitory avoidance task of memory has been used to examine retrieval of memory formation, 24 h after training in male Wistar rats. RESULTS The results indicate that post-training administration of morphine (7.5 mg/kg) impaired memory retrieval, but not in the animals, which received previous repeated morphine (7.5 and 10 mg/kg) injections followed by morphine withdrawal. Repeated co-administration of NMDA (7.5 and 10 ng/rat, intra-CA1) with an ineffective dose of morphine (5 mg/kg), once daily for three days reversed morphine-induced amnesia. Repeated bilateral intra-CA1 microinjections of NMDA, once daily for three days followed by a five-day washout had no effect on the expression of amnesia produced by post-training morphine. Three-day administration of the NMDA receptor antagonist, D-AP5 (0.5 - 2 µg/rat, intra-CA1) followed by a five-day washout had no effect on morphine-induced amnesia. On the other hand, intra-CA1 microinjections of the same doses of D-AP5 prior to injection of 7.5 mg/kg of morphine (per day×3 days) decreased the reversal of morphine-induced amnesia. CONCLUSION These data imply that the dorsal hippocampal NMDA receptor mechanism(s) may modulate the effect-induced by repeated morphine administration on a challenge dose of morphine-induced amnesia.