Low level lead exposure increases sensitivity to the stimulus properties of dopamine D1 and D2 agonists.
To examine the impact of Pb exposure on dopaminergic (DA) function, weanling rats were chronically exposed to 0, 50 or 250 ppm Pb acetate in drinking water. At 3 months of age, the rats were trained to discriminate the stimulus properties of either the D1 agonist SKF38393 (3.0 mg/kg i.p.; D1/sal) or the D2 agonist quinpirole (0.05 mg/kg i.p., D2/sal) from saline using a standard two-lever operant food-reinforced drug discrimination paradigm. Lead-exposed rats learned the discriminations faster than respective controls. Moreover, they exhibited greater levels of drug lever responding to lower doses of the training drugs (D1/sal and D2/sal), and to selected doses of other direct and indirect DA agonists (D2/sal only), including apomorphine, cocaine and (+)-amphetamine, and less blockade of drug lever responding by haloperidol (D2/sal). Taken together, these findings are consistent with a generalized DA supersensitivity. There were no differential Pb effects when non-DA compounds including morphine, pentobarbital and MK-801 were substituted for the training drugs, indicating the selectivity of the DA effects in the context of these experiments, and the improbability of a non-specific behavioral causation. Pb-exposed rats in the D2/sal group also showed a pronounced enhancement of drug lever responding when NMDA was substituted for quinpirole, suggesting the possibility of a Pb-induced NMDA supersensitivity as well.
Cory-Slechta
D A
DA
Department of Biophysics, University of Rochester School of Medicine and Dentistry, NY 14642.
Widzowski
D V
DV
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D004357:Drug Synergism; D004873:Ergolines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005793:Generalization, Psychological / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D007854:Lead / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D019257:Quinpirole; D051381:Rats; D011954:Receptors, Dopamine / Q000502:physiology*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu
D015259:Dopamine Agents; D004873:Ergolines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D019257:Quinpirole; D007854:Lead; D016202:N-Methylaspartate; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016291:Dizocilpine Maleate; D009020:Morphine; D010424:Pentobarbital; D003042:Cocaine; D006220:Haloperidol; D001058:Apomorphine; D003913:Dextroamphetamine