BEHAVIORAL TOXICITY OF LEAD--A PHARMACOLOGICAL ANALYSIS

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DESCRIPTION: (Pb) levels that can be linked to deleterious behavioral effects. The mechanism(s) by which these effects are produced, however, are still unknown. Proposed cellular or biochemical bases have remained hypothetical. Studies from the past period of support of this application, however, now directly tie changes in mesolimbic dopamine (DA) systems in nucleus accumbens to one repeatedly described behavioral effect of Pb exposure in experimental animal studies, namely changes in Fixed Interval (FI) schedule controlled behavior. This relationship is indicated by the finding that: 1) inactivation of DA receptors in nucleus accumbens but not dorsal striatum selectively decreases FI response rates in normal rats; and 2)nucleus accumbens but not dorsal striatum demonstrates selective vulnerability to the decreases in DA binding produced by postweaning Pb exposure. Thus, nucleus accumbens DA systems appear to be critical to the mediation of normal FI performance and express preferential vulnerability to Pb effects on DA receptor binding. The proposed studies examine this potential link hypothesizing that: 1) DA receptor activation or inactivation in nucleus accumbens should also be selectively involved in FI performance of postweaning Pb-treated rats even though the magnitude of the effects may differ; 2) the increases in FI response rates resulting from post weaning Pb exposure will be associated with increased DA availability in nucleus accumbens. Individual differences in FI rate increases produced by Pb may positively correlate with the extent of increased DA availability; 3) nucleus accumbens systems may contribute to the deficits in learning associated with postweaning Pb exposure. These hypotheses will be tested using approaches including behavioral assessments of FI performance or learning following microinjections of DA agonists or antagonists into nucleus accumbens or dorsal striatum, in vivo electrochemistry to determine the extent of Pb-induced changes in DA availability, and receptor autoradiography to examine corresponding changes in DA binding sites. If these hypotheses are borne out, they will provide specific and circumscribed direction to studies of mechanisms initiating this cascade of DA system changes. These studies will also further enhance the understanding of DA mechanisms of cognitive function and thus yield information directly relevant to other neurological conditions associated with such behavioral effects. They will likewise provide guidance for behavioral and/or chemical therapeutics for Pb-induced behavioral toxicity.