BACKGROUND NMDA-receptor antagonists may be of potential therapeutic use in several states of disease. It has been reported that drugs like MK-801 can potentiate the rewarding effects of other drugs, which may complicate the therapeutic use of this class of drugs. However, since MK-801 appears to be an "atypical" drug in several respects, other NMDA-receptor antagonists may not share this effect of MK-801. OBJECTIVE We tested the effects of memantine, a clinically used NMDA-receptor antagonist, in a paradigm that has previously shown the reward-potentiating effects of MK-801 to see if this drug would yield qualitatively comparable results. METHODS The effects of memantine on morphine- and cocaine-induced potentiation of brain stimulation reward were examined, using the rate-free curve-shift paradigm. RESULTS Low doses of morphine (2.5 mg/kg) and cocaine (5 mg/kg) produced moderate decreases in the reward threshold frequency reflected in moderate leftward shifts of the function relating response rate to stimulation frequency. These effects were not altered by co-administration of an intermediate dose of memantine (5 mg/kg), but maximum response rate was significantly increased by these drug combinations. Higher doses of morphine (7.5 mg/kg) and cocaine (10 mg/kg) had stronger effects on the rate-frequency function and reward threshold. These effects were enhanced by co-administration of a high dose of memantine (10 mg/kg), while the effects on maximum response rate were less pronounced. CONCLUSIONS These results demonstrate that fairly high doses of memantine and morphine or cocaine have to be combined in order to observe an enhancement of the latter drugs' potentiation of brain stimulation reward. In this respect, memantine differs markedly from MK-801, another non-competitive NMDA-receptor antagonist which has been shown to interact with morphine and cocaine at very low doses.