Estimates indicated that lead (Pb) remains a public health problem for 1 in 6 children in the U.S. But the effects of current environmental Pb levels may be more pervasive than encompassed by a simple association between Pb and cognitive function in children. Experiments supported by this application over the past 4 years examining Pb-induced changes in NMDA receptor (glutamate;GLU)-mediated function, in conjunction with our studies of Pb-induced changes in dopaminergic (DA) function, suggest a pattern of neurochemical changes that preferentially targets one of the 2 major long-length DA systems, i.e., the mesolimbic (MESO) system, while leaving nigrostriatal DA systems unaffected. Specifically, chronic low- level post weaning Pb exposure appears to both attenuate GLU input to nucleus accumbens (NAC) and enhance synaptic DA levels in NAC, changes that would alter DA/GLU balance in MESO system., and have potentially profound implications for the various behavioral functions it mediates. It is notable that a strikingly similar pattern of changes has been proposed to underlie schizophrenia, that MESO systems mediate behavioral sensitization, a phenomenon considered to be involved in drug abuse, and that MESO systems are critical to the mediation of properties of reward, learning and memory functions, and attentional processes. The current application seeks to determine the functional significance of Pb-induced MESO system changes, i.e., whether they serve as a mechanism for Pb's known behavioral toxicity, and whether they engender a broader pattern of behavioral deficits, perhaps contributing to other behavioral dysfunctions associated with MESO systems. It does so by testing the hypothesis that: 1) in addition to its known behavioral toxicity, Pb will impact other behavioral functions mediated by MESO systems, including locomotor activity and behavioral sensitization; 2) that MESO system disruptions mediate Pb-induced changes in FI performance and spatial/reversal learning, and that 3) Pb will attenuate MK-801-induced alterations in evoked DA overflow. These hypotheses will be assessed using behavioral baselines in conjunction with systemic and intra-NAC pharmacological probes and in vivo electrochemistry. The proposed experiments will further determine the extent of Pb as a risk factor, further elucidate and circumscribe mechanisms of Pb-induced behavioral toxicity, contribute to our understanding of MESO system mediation of complex behaviors, providing information of direct relevance to other neurological disturbances associate with these systems, and provide a basis for assessing chemical and behavioral therapeutic strategies for MESO system alterations.
