Systemic administration of a variety of N-methyl-D-aspartate (NMDA) receptor antagonists inhibits morphine's rewarding properties in the conditioned place preference test. In this study, we investigated the anatomical loci implicated in the inhibition of expression of morphine's reward by bilateral microinjections of a selective NMDA antagonist into the mesolimbic areas, including ventral tegmental area and nucleus accumbens. During conditioning, injections of 1 mg/kg morphine were associated with placing rats in one chamber of the place preference box; the exposures to the other chamber were associated with placebo administration. On the test day, drug-free control subjects demonstrated a marked preference for the morphine-associated chamber. Systemic administration of 5 mg/kg and 10 mg/kg of the competitive NMDA antagonist, NPC 17742 (2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid), significantly reduced the expression of morphine-induced conditioned place preference; the dose of 10 mg/kg produced also an inhibition of locomotor activity. Similar attenuation of the expression of morphine-induced conditioned place preference was observed in rats receiving 15.6 and 62.5 ng/0.5 ml side of NPC 17742 injected bilaterally into the nucleus accumbens and ventral tegmental area. While the higher intra-accumbal dose of NPC 17742 produced behavioral stimulation, intra-tegmental injection did not affect locomotor activity. These findings suggest that activation of NMDA receptors in the nucleus accumbens and ventral tegmental area is necessary for the elicitation of approach by environments previously associated with morphine's rewarding action.