The consequences of asymptomatic lead (Pb) exposure in man and the development of rational approaches for their prevention and treatment are matters of serious social concern. Research to characterize the behavioral impairments in children have described several suspected psychological effects. However, the magnitude and duration of exposure necessary to produce these deficits and the mechanisms underlying their manifestation have remained elusive. The issue remains a serious scientific concern because of the pervasive presence of Pb in many urban environments and the fact that animal studies have suggested the occurrence of behavioral alterations even when blood Pb values are low. Hypotheses regarding the effects of chronic developmental exposure on CNS neurotransmitter function in animals are poorly developed. The use of pharmacological agents to unmask subtle CNS dysfunctions has been fruitful in discriminating Pb toxicity in behavioral paradigms, but has not been advantageously applied to neurochemical measures. This research proposal is designed to extend previous findings of dopaminergic alterations in exposed rats to other dopaminergic drugs. Subsequently, the research will determine to what degree the Pb-induced changes are due to altered function of presynaptic receptors on dopaminergic nerve terminals and their relationship to associated changes in dopamine (DA) synthesis. These studies will utilize microdissection of rat brain structures in order to study discrete DA neuronal systems, liquid chromatography with electrochemical detection and scintillation counting to quantify drug-induced changes in DA content and synthesis rate, intravenous administration of radiolabeled amino acid precursor to measure synthesis, and a synaptosomal model to investigate specific synaptic processes. An animal model of asymptomatic Pb exposure will be utilized with hematologic and nutritional characteristics comparable to those in the pediatric population at risk. The proposed research will identify synaptic sites of impairment and indicate the importance of interactive influences produced by other impinging neurotransmitter systems by the selective use of specific neuropharmacological agents. As a result of information obtained on toxic mechanisms, more effective treatment of neurotoxicity can be devised as well as more appropriate methods for clinical evaluation of individuals at risk.
