Postweaning Pb exposure has been associated with subsensitivity to the stimulus properties of the non-competitive NMDA receptor complex antagonist MK-801 (Cory-Slechta, 1995a). This study sought to determine whether Pb exposures occurring postnatally, i.e., during the primary period of development of many NMDA receptor subunits, would alter the nature of these glutamatergic system changes. Rat pups were exposed to Pb from 0-21 days of age via lactating dams consuming solutions of 0, 100 or 350 ppm Pb acetate. Beginning at 9 mos of age, rats were trained to discriminate 0.05 mg/kg MK-801 from saline using standard operant drug discrimination procedures. Following acquisition of the discrimination, various doses of MK-801, the non-competitive antagonist phencyclidine (PCP), the competitive antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP) and the agonist N-methyl-D-aspartate (NMDA) were substituted for 0.05 mg/kg MK-801 and percent MK-801 lever responding to each determined. Subsequently, a drug washout period was imposed, after which MK-801 dose-effect curves were re-established. Increasing doses of MK-801 and PCP produced dose-dependent increases in MK-801 lever responding resulting in full substitution, whereas CPP and NMDA evoked primarily saline-appropriate responding. Pb exposure was associated with enhanced MK-801 sensitivity during the pre-washout phase, but attenuated sensitivity following MK-801 washout. In both cases, however these effects were of relatively modest magnitude. No systematic Pb-related changes in response to PCP, CPP or NMDA were observed. These data raise the possibility, particularly when considered in relation to studies based on other Pb exposure protocols, that NMDA receptor changes may depend upon ongoing or extant Pb exposures, or that postnatal exposure effects on this system may be largely reversible. In addition, the differential nature of the effects seen with postnatal vs postweaning exposure (Cory-Slechta, 1995a) underscores the significance of the developmental period of exposure to Pb effects on the NMDA receptor complex.