BEHAVIORAL TOXICITY OF LEAD--A PHARMACOLOGICAL ANALYSIS

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Undue lead (Pb) exposure remains one of the most pressing pediatric environmental health problems of this country, and yet the neurobiological basis of its behavioral toxicity remains unknown. Over the past 2 years, this application sought to confirm, using drug discrimination (DD) and receptor binding studies, the then prevailing hypothesis based on d-amphetamine studies that Pb exposure resulted in a functional dopaminergic (DA) subsensitivity which could underlie it's behavioral manifestations. However, our DD and receptor binding studies, using selective D1 and D2 agonists rather than d-amphetamine, revealed a functional DA supersensitivity which may be related to DA receptors in the nucleus accumbens, and which appears to differ with respect to D1 receptor involvement in postnatal vs. postweaning exposures. One postulated explanation for the this pattern of outcomes that is also consistent with previously reported d-amphetamine subsensitivity, is that these effects are achieved through inhibitory autoreceptor agonism. This renewal application relies primarily on DD procedures and receptor binding assays to first qualitatively confirm these observations in light of some gaps in our initial findings, to then further characterize the nature of this DA supersensitivity and finally to pursue hypothesis relating to nucleus accumbens as a site of these effects and inhibitory autoreceptor agonism as their basis. DD studies will be used to: qualitatively confirm these initial observations, determine whether they represent a direct effect on DA systems or occur via neurotransmitter interactions, whether D1 supersensitivity is a direct effect or results from D1/D2 receptor interactions, the extent to which D2 supersensitivity includes both autoreceptor and postsynaptic receptor components, whether a functional reuptake blockade subsensitivity consistent with autoreceptor agonism occurs with d-amphetamine and GBR12909 drug stimuli, the extent to which Pb-induced DA supersensitivity is mimicked by chronic autoreceptor agonism and is reversed by chronic autoreceptor antagonism, and adult susceptibility. Receptor binding studies, to be carried out concurrently with DD studies, will provide specific information with respect to the time-course of nucleus accumbens and striatal Bmax changes and their correspondence to DD sensitivity changes. The application also proposes a time-course assessment of Pb-induced changes in DA turnover and DA levels to provide information relevant to the autoreceptor agonism basis of such effect, and the incorporation of two additional behavioral baselines to determine if Pb-induced DA supersensitivity is a generalized behavioral supersensitivity. It is the more precise understanding of the nature and basis of Pb-induced DA supersensitivity to be achieved by these proposed studies that will permit the design of future experiments that directly examine the relationships between DA changes and the behavioral effects of Pb, experiments which will determine the importance of Pb-induced changes in DA systems as a neurobiological basis of Pb- induced behavioral toxicity.