Recently published cellular and biochemical studies suggest that Pb exposure may impair learning and memory functions through an inhibitory action on the NMDA receptor complex. this notion of an NMDA-based mechanism for the behavioral toxicity of Pb has appeal because: a) it could account for behavioral toxicity in response to Pb exposures either early in development or under conditions of occupational exposure; b) it could explain the preferential vulnerability to Pb of learning relative to performance functions; c) it is consistent with reports of preferential accumulation of Pb in hippocampus, an area of NMDA receptor density; d) it would provide a mechanism for cognitive deficits in the absence of a defined morphological lesion. For such a contention to have credence or clinical significance, however, requires that NMDA-based sensitivity be altered at a behavioral level and/or that compounds acting at the NMDA receptor complex could alter Pb-induced changes in learning. New data from this laboratory supporting that contention include an attenuation and potentiation, respectively, of the accuracy-impairing effects of the non-competitive NMDA antagonist MK-801 and the glutamate agonist NMDA in Pb-exposed rats relative to controls on a multiple schedule of repeated learning (repeated acquisition) and performance. The proposed experiments seek, first, to determine using drug discrimination and receptor autoradiography procedures, the nature of Pb- induced changes in NMDA and MK-801 sensitivity at the level of the whole animal, any correspondence between sensitivity changes and NMDA receptor complex changes, and the conditions under which sensitivity changes occur, including the role of developmental period of exposure (including postnatal, postweaning and adult), associated blood and brain Pb levels, and the importance of a prior behavioral history of drug discrimination. Using a multiple schedule of repeated acquisition (learning) and performance combined with receptor autoradiography, the proposal also seeks to further explore the role of Pb-induced changes in the NMDA receptor complex to Pb-induced learning impairments, by determining whether other noncompetitive antagonist effects on this baseline are also attenuated by Pb exposure, whether such attenuation also occurs in response to competitive NMDA antagonists, and whether subchronic noncompetitive NMDA antagonist administration in normal untreated rats produces a pattern of learning impairments that mimics that produced by Pb exposure per se. Taken together, these experiments will yield a more precise understanding of the scope of Pb-induced changes in NMDA receptor complex function at the level of the whole animal, any receptor basis for such effects, and an increased understanding of the extent to which these effects have clinical significance for the behavioral toxicity of lead, particularly for learning impairments.
