Our previous studies showed that agmatine inhibits morphine-induced conditioned place preference, locomotor sensitization and drug discrimination in rats. In the present study, we investigated the effects of agmatine on intravenous morphine self-administration in rats. At a dose of 80 mg/kg/infusion, agmatine did not substitute for intravenous morphine (0.5 mg/kg/infusion) self-administration, suggesting that agmatine itself has no reinforcing effect. However, pretreatment with agmatine (40 or 80 mg/kg, i.g.) significantly inhibited the acquisition of intravenous morphine self-administration as assessed by the nose-poke response and morphine intake. The mean number of days required to meet the acquisition criteria for intravenous morphine self-administration was significantly prolonged. After acquisition of intravenous morphine self-administration, chronic administration of agmatine (40 or 80 mg/kg x 30 days, bid, i.g.) during the extinction period significantly prevented the re-acquisition of intravenous morphine self-administration. The ability of agmatine to inhibit the acquisition and re-acquisition of intravenous morphine self-administration suggests a possible use of agmatine in the treatment of opioid dependence.