Functional alterations in dopamine systems assessed using drug discrimination procedures

Numerous studies have suggested that Pb-induced perturbations of dopamine (DA) systems and DA functions could underlie the behavioral impairments attributed to Pb exposure. However, the precise nature of the effects of Pb on DA systems, either at the receptor/biochemical level or at the behavioral level have never been precisely delineated, much less interrelated. Substantial advances in the understanding of DA neuropharmacology provide new opportunities to more precisely elaborate Pb-induced changes in DA systems and DA function. Recently completed studies from our laboratories using drug discrimination procedures indicate that low-level postweaning Pb exposure produces a functional DA supersensitivity manifest at both the D1 and D2 receptor subtypes. Postnatal Pb exposure likewise induces functional DA supersensitivity, although this effect appeared to be restricted to the D2 receptor subtype. In conjunction with the drug discrimination studies, standard homogenate receptor binding assays of D1 and D2 receptors carried out in 5 different brain regions (striatum, nucleus accumbens, frontal cortex, midbrain and cerebellum) suggested a correspondence between D2 DA behavioral supersensitivity and Bmax changes found in nucleus accumbens, suggesting it as a possible site for Pb-induced supersensitivity to DA agonist stimulus properties. Collectively, the nature of the changes in DA sensitivity in the drug discrimination studies and the changes in D1 and D2 receptor number raise the possibility that Pb could, in part, produce a net functional autoreceptor agonism.