Relationships between Pb-induced changes in neurotransmitter system function and behavioral toxicity.

Lead (Pb) exposure impairs learning and results in changes in Fixed Interval (FI) schedule-controlled behavior in experimental animal studies. Studies from our laboratory suggest a major involvement of dopamine systems, and perhaps nucleus accumbens, in the FI performance changes. Dopaminergic (DA), but not other classes of compounds differentially alter FI response rates of control and Pb-treated rats. Marked changes in nucleus accumbens but not striatal D2 and dopamine uptake sites occur in response to Pb. Further, the irreversible DA antagonist EEDQ microinjected into nucleus accumbens but not into striatum suppresses FI performance. In contrast, glutamatergic system disturbances appear to play a key role in the learning impairments caused by Pb. Glutamatergic (GLU) compounds differentially alter learning accuracy levels in control vs. Pb-treated rats, whereas DA compounds do not. Accuracy levels in the learning paradigm were positively correlated with numbers of MK-801 and glutamate binding sites in control rats; these correlations were reversed by Pb exposure. Future studies should be designed to confirm these relationships, to examine the brain regions involved, to determine the extent to which other behaviors known to be mediated by GLU/DA mesocorticolimbic systems are disrupted by Pb, and to address the significance of developmental period of exposure to these effects as well as their reversibility.