LEAD-INDUCED CHANGES IN DOPAMINE D-1 SENSITIVITY - MODULATION BY DRUGDISCRIMINATION-TRAINING

Prior studies have reported that Pb exposure results in enhanced sensi tivity to both D-1 and D-2 dopamine agonists as indicated by left shif ts of the dose-effect Functions for the discrimination of these agonis ts from saline in drug discrimination procedures (Cory-Slechta and Wid rowski, 1991). To further determine mechanisms of such Pb-induced chan ges in dopamine system functions, this study evaluated the potential c ontribution to Pb-induced D-1 supersensitivity of:i) synergistic D-1-D -2 receptor interactions, and ii) the effects of the chronic D-1 agoni st administration inherent in the drug discrimination procedures thems elves. As in Cory-Slechta and Widzowski (1991), rats exposed from wean ing to 50 or 150 ppm Pb acetate in drinking water and trained using st andard operant drug discrimination procedures to discriminate 6.0 mg/k g of the partial D-1 agonist SKF38393 from saline showed greater sensi tivity to SKF38393 (left-shifted dose effect curves) than did the 0 pp m group. To determine the role of D-1/D-2 interactions in this superse nsitivity, SKF38393 dose-effect curves of the groups were compared in the presence and absence of a dose of 0.04 mg/kg of the D-1 antagonist haloperidol. The impact of the chronic administration of the D-1 agon ist utilized in drug discrimination training was determined by compari ng the dose-effect curves of the groups before and after a 24 day peri od of discontinuation of drug discrimination training. D-1/D-2 interac tions do not appear to contribute to Pb-induced enhancement of sensiti vity to the D, agonist SKF38393, as it was maintained even in the pres ence of the D-2 antagonist haloperidol. Discontinuation of drug discri mination training resulted in sensitization in control but not Pb-trea ted rats, a pattern indicative of Pb-induced D-1 subsensitivity. These data raise questions about the depletion of dopamine (DA) availabilit y as a mechanism of Pb-induced alterations in DA system function and s uggest that Pb-induced D-1 supersensitivity may represent altered effe cts of chronic D-1 administration imposed on DA systems modified by Pb exposure per se. (C) 1996 Inter Press, Inc.