The deleterious effects of postnatal lead (Pb) exposure on neural development, synaptic plasticity, and cognitive function have been well documented in laboratory animals. While the exact mechanisms by which Pb produces long-lasting neurotoxicity remain unknown, recent evidence suggests that Pb may interact with and/or disrupt the N-methyl-D-aspartate/phencyclidine receptor complex and the associated ion channel. In addition to perturbations of excitatory amino acid neurotransmission, chronic Pb exposure may also have deleterious effects on inhibitory mechanisms such as that provided by purinergic neuromodulation. In order to further examine the possibility that alterations of both excitatory and inhibitory neurotransmission may contribute to the neurotoxic actions of Pb, the effects of early Pb exposure on ligand binding to postnatal rat brain N-methyl-D-aspartate (NMDA), phencyclidine (PCP), and adenosine A, receptors were examined using quantitative autoradiography techniques. Rat pups nursed mothers exposed to 4% PbCO, in their diet or a Na,CO, control diet from postnatal day 1 (PI) to P25. At P25, rats were sacrificed and the regional distributions of brain NMDA, PCP, and adenosine A, receptors were examined. Chronic lead exposure was found to produce a specific increase in [,H]CGP 39653 binding to NMDA receptors in the hippocampus. [3H11-(1-[2-thienyl)cyclohexyl]-piperdine ([3H]TCP) binding to PCP receptors was largely unaffected by the chronic Pb treatment. In contrast, [3H]cyclohexyladenosine ([3HlCHA) binding to adenosine A, receptors was markedly reduced in many brain regions with the largest decreases observed in the cerebellum. These results indicate that neonatal Pb exposure produces a specific alteration of both excitatory and inhibitory neuromodulatory mechanisms in the postnatal rat forebrain that may underlie the behavioral hyperactivity and increased seizure sensitivity associated with Pb neurotoxicity.