Use of pharmacological challenges to disclose neurobehavioral deficits

Delineation of the neurotoxic effects of various environmental agents is often complicated by the considerable compensatory capacity of the central nervous system (CNS). Moreover, the degree to which such compensation occurs may be critical when one is examining dosages near the threshold for biological effect. A current approach has been to use pharmacological agents to unmask deficits that are reflected in performance on subsequent behavioral tasks. This noninvasive manipulation may also provide insight into the underlying neurochemical substrates of the CNS insult. This procedure has been successfully applied in experiments examining a wide range of compounds (e.g., lead, mercury, acrylamide, carbon disulfide) in animals exposed during development or adulthood. Even more striking is the ability of this technique to disclose latent effects, i.e., effects that are demonstrable long after exposure has ceased. This laboratory has attempted to further elaborate the use of pharmacological probes. Utilizing a drug discrimination paradigm, we have investigated the altered amphetamine sensitivity exhibited by offspring exposed to lead early in life. This paradigm has been frequently employed in psychopharmacology and has been well validated as a tool for assessing drug response thresholds. Furthermore, additional pharmacological manipulations (agonists, depletors, blockers) can be imposed on the original drug discrimination to refine hypotheses regarding neurochemical alterations underlying the shifts observed in drug discrimination thresholds.