Time course and regional basis of Pb-induced changes in MK-801 binding: reversal by chronic treatment with the dopamine agonist apomorphine but not the D1 agonist SKF-82958.
In the present study we attempted to further define the time course and regional specificity of lead (Pb)-induced changes in the NMDA receptor complex and the influence of dopaminergic system modulations on these changes. Autoradiographic measurements of alterations in MK-801 binding, as evaluated under four different activation conditions (none, spermidine, glycine, or maximal activation), were performed in medial frontal cortex, dorsal striatum, and nucleus accumbens of male rats after 2 weeks or 8 months of chronic postweaning (from 21 days of age on) exposure to 0, 50, or 150 ppm Pb acetate in drinking water. The 8-month groups also received chronic intermittent intraperitoneal injections of saline, or of the dopamine (DA) agonist apomorphine or the D1 agonist SKF-82958 2-3 times per week beginning at 60 days of age. Two weeks of 50 ppm Pb exposure resulted in small but significant increases in MK-801 binding under conditions of glycine or spermidine activation, whereas decreases were observed in response to 150 ppm under conditions of no or maximal activation in all regions. After 8 months of Pb, concentration-dependent decreases in MK-801 binding were observed across regions under all activation conditions. These effects were noted at blood Pb concentrations averaging as low as 16 microg/dl. Pb-induced decreases in MK-801 binding were either partially or fully reversed by chronic intermittent treatment with the DA agonist apomorphine but not by the D1 agonist SKF-82958, implicating D2-based mechanisms in this reversal. Combined findings from this and previous studies based on this exposure protocol indicate a Pb-induced pattern of widespread hypoglutamatergic function accompanied by increased DA function in mesolimbic systems, a pattern of changes reminiscent of those proposed to underlie schizophrenia. Such findings suggest that Pb exposure, even at current environmental levels, could be a risk factor for behavioral and/or neurological disturbances arising from imbalances of glutamate/dopamine function in mesocorticolimbic systems.
Cory-Slechta
D A
DA
Department of Neurobiology and Anatomy, University of Rochester School of Medicine, New York 14642, U.S.A.
McCoy
L
L
Richfield
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EK
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D004334:Drug Administration Schedule; D007854:Lead / Q000494:pharmacology*; D008297:Male; D009994:Osmolar Concentration; D051381:Rats; D011919:Rats, Inbred Strains; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D013997:Time Factors; D014018:Tissue Distribution
D001552:Benzazepines; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D007854:Lead; D016291:Dizocilpine Maleate; C071262:SK&F 82958; D001058:Apomorphine