Although the hypothesis has repeatedly been posed that attention deficits underlie the cognitive impairments produced by Pb, no systematic examination of this assertion has been undertaken in either human cohorts of experimental animals. The current studies directly address in rats the hypothesis that impulsivity/aversion to delay, one of the three clinically- defined sympton domains of attention deficit disorder, may be a particular target of Pb, based on our comparative observations of Pb effects on a fixed ratio (FR) waiting for reward paradigm and a sustained attention task. On the FR wait paradigm, free food deliveries were available at increasing delays following the completion of an FR 50; any response during the waiting component reset the FR requirement. Mean waiting times of Pb-treated rats were 50 percent shorter than controls. While other explanations are feasible, these results could reflect an aversion to delay which was terminated by a response resetting the FR component. These same Pb exposures were without systematic effect in sustained attention task. Impulsivity, as measured in children using self-control procedures, is predicted by increased fixed interval (FI) response rates. Pb exposure reliably increases FI response rates in animal models. Thus, Pb exposure should likewise increase impulsivity in self-control procedures. This proposal seeks to further evaluate the effect of Pb on impulsivity, the role of aversion to delay in mediating it, and the importance of developmental period of exposure in such effects. Studies show that nucleus accumbens (NAC) dopamine (DA) systems modulate FI response rates. Thus, NAC DA should likewise modulate impulsivity if FI response rates are predictive of impulsivity. These studies will also determine the extent to which NAC DA systems modulate impulsivity in a self-control paradigm. Using combined behavioral/microinjection approaches, three hypotheses will be examined: 1) If Pb exposure produces impulsivity, it should increase the choice of small immediate rewards over larger but delayed rewards in self-control paradigm; 2) Delay aversion rather than alternative behavioral mechanisms accounts for the shorter wait times of Pb-exposed rats on the FR wait paradigm; and 3) NAC DA activity will modulate levels of impulsivity. Collectively, these studies will i) enhance the understanding of impulsivity/delay aversion under both normal and Pb-exposed conditions; ii) provide a more precise basis for behavioral and chemical therapeutic strategies; iii) provide models to assess genetic or environmental risk factors in addition to Pb which can be directly extrapolated to pediatric cohorts.
