Lead-induced changes in dopamine D1 sensitivity: modulation by drug discrimination training.
Prior studies have reported that Pb exposure results in enhanced sensitivity to both D1 and D2 dopamine agonists as indicated by left shifts of the dose-effect functions for the discrimination of these agonists from saline in drug discrimination procedures (Cory-Slechta and Widzowski, 1991). To further determine mechanisms of such Pb-induced changes in dopamine system functions, this study evaluated the potential contribution to Pb-induced D1 supersensitivity of:i) synergistic D1-D2 receptor interactions, and ii) the effects of the chronic D1 agonist administration inherent in the drug discrimination procedures themselves. As in Cory-Slechta and Widzowski (1991), rats exposed from weaning to 50 or 150 ppm Pb acetate in drinking water and trained using standard operant drug discrimination procedures to discriminate 6.0 mg/kg of the partial D1 agonist SKF38393 from saline showed greater sensitivity to SKF38393 (left-shifted dose effect curves) than did the 0 ppm group. To determine the role of D1/D2 interactions in this supersensitivity, SKF38393 dose-effect curves of the groups were compared in the presence and absence of a dose of 0.04 mg/kg of the D2 antagonist haloperidol. The impact of the chronic administration of the D1 agonist utilized in drug discrimination training was determined by comparing the dose-effect curves of the groups before and after a 24 day period of discontinuation of drug discrimination training. D1/D2 interactions do not appear to contribute to Pb-induced enhancement of sensitivity to the D1 agonist SKF38393, as it was maintained even in the presence of the D2 antagonist haloperidol. Discontinuation of drug discrimination training resulted in sensitization in control but not Pb-treated rats, a pattern indicative of Pb-induced D1 subsensitivity. These data raise questions about the depletion of dopamine (DA) availability as a mechanism of Pb-induced alterations in DA system function and suggest that Pb-induced D1 supersensitivity may represent altered effects of chronic D1 administration imposed on DA systems modified by Pb exposure per se.
Cory-Slechta
D A
DA
Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, New York 14642, USA.
Pokora
M J
MJ
Fox
R A
RA
O'Mara
D J
DJ
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology*; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology*; D004347:Drug Interactions; D006220:Haloperidol / Q000494:pharmacology; D007854:Lead / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000502:physiology
D018491:Dopamine Agonists; D009942:Organometallic Compounds; D017447:Receptors, Dopamine D1; D007854:Lead; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D006220:Haloperidol; C008261:lead acetate