Triethyllead (TEL) is a neurotoxic organometal that produces behavioral and neurological alterations in both laboratory animals and man. Despite the prevalence of this compound in the environment and the repeated episodes of human poisoning, the sites and mechanisms of action of TEL-induced neurotoxicity remain undetermined. The experiments outlined in this proposal are designed to address the hypothesis that TEL enhances dopamine-mediated processes in specific neural loci. More specifically, it is suggested that TEL augments D1-mediated receptor events in mesolimbic regions that participate in the control of locomotor behavior. This hypothesis is consitent with neurochemical, pharmacological and behavioral studies demonstrating an augmented behavioral response to both direct (apomorphine and indirect-acting (d-ampehtamine) dopamine agonists concomitant with an enhanced reactivity of dopamine-stimulated cyclase activity in mesolimbic sites, following acute exposure to TEL. Furthermore, the expression of TEL's behavioral effects can be modified by pharmacological manipulation of brain dopamine systems. Because basal levels of cyclase activity and motor activity are not affected by TEL, it is likely that the responsivity of dopamine systems is primarily affected by this neurotoxicant. That is, an appropriate stimulus will produce an exaggerated or supersensitive response in affected neural regions. A general principle organizing this proposal is that neurotoxic insult may produce alterations in dopaminergic function that are only detectable in specific neuroanatomical regions and in subpopulations of dopamine receptors. The primary goal of these studies is to further delineate the sites and mechanisms of TEL-induced alterations in brain dopamine systems. This information will be useful for understanding the biological substrates of organolead toxicity. Furthermore, at a more general level, these studies will help to define the ways in which subpopulations of dopamine receptors react and adapt to toxic insult.
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