This proposal seeks to test the hypothesis that lead (Pb) exposure results in a functional dopaminergic (DA) subsensitivity. This hypothesis is based on two sources of data: 1) experiments indicating that Pb-exposed rats require higher doses of d-amphetamine than controls to distinguish the drug from saline in drug discrimination (DD) paradigms; 2) multiple reports that Pb-exposed organisms exhibit attenuated effects of d-amphetamine in a variety of behavioral paradigms. These studies, however, offer several alternative explanations as well. The question has yet to be resolved definitively, however, despite wide-ranging mechanistic implications. We propose to examine this hypothesis in animals trained to discriminate either a DA D1 agonist, or a DA D2 agonist from saline, using a standard 2- lever DD paradigm. The use of selective D1 and D2 receptor ligands, rather than a compound with mixed properties such as amphetamine, is expected to provide precise information on the extent of any functional DA subsensitivity, as well as it's exact nature. Previous work suggests that critical period of Pb exposure for these dopaminergic effects to be postnatal. This application will compare early developmental Pb exposures to those initiated later in development, in light of contrasting evidence which indicates that susceptibility extends t adult animals. The possibility that altered dopaminergic DD performance in Pb-exposed animals may result from a generalized impairment of discriminative capacity will be evaluated by using a cholinergic DD: since Pb exposure has been postulated to result in cholinergic supersensitivity, the resulting DD effects should be opposite in direction to those observed with DA agonists. Finally, the extent to which Pb-induced DA subsensitivity can be modulated by behavioral context will be determined by comparing DA DD dose-effect functions to those obtained on other behavioral baselines, specifically, a Fixed- Interval schedule of food reinforcement and a delayed alternation paradigm. From these experiments, we expect to attain a more comprehensive, integrated assessment of Pb-induced DA subsensitivity which can serve as the basis for future experiments designed to directly evaluate their relationship to Pb-induced behavioral toxicity.
