Lead-induced changes in NMDA receptor complex binding: correlations with learning accuracy and with sensitivity to learning impairments caused by MK-801 and NMDA administration.
This study sought to further evaluate potential mechanistic relationships between Pb-induced alterations in glutamate neurotransmission and behavioral toxicity. It examined correlations between Pb-induced changes in [3H]MK-801 and [3H]CGP-39653 binding sites in 4 different brain regions (frontal cortex, dentate gyrus, CA1 and striatum) and (1) changes in learning accuracy on a multiple repeated acquisition and performance schedule, and (2) sensitivity to the accuracy-impairing effects of MK-801 and NMDA on this learning baseline. All data were obtained from a single population of rats that had been chronically exposed from weaning to 0, 50 or 250 ppm Pb acetate in drinking water and demonstrated selective learning impairments and altered sensitivity to the effects of MK-801 and NMDA on learning accuracy. Pb exposure decreased MK-801 binding and possibly increased CGP-39653 binding, effects statistically significant in some brain regions, but generally exhibiting similar trends across regions. At 0 ppm, higher levels, particularly of MK-801 binding, were associated with higher accuracy levels in the learning paradigm and with greater decrements in learning accuracy following MK-801 or NMDA administration. These linear correlations were negated and in some cases even reversed by 50 and 250 ppm Pb, an effect that might be attributable to an alteration of NMDA receptor complex subunit composition and thus, ligand binding. Of the 4 brain regions examined, striatal MK-801 binding proved to be the best predictor of learning accuracy levels. These data provide additional support for an involvement of the NMDA receptor complex in Pb-induced learning impairments. The fact that these effects were noted most frequently in striatum also raises the possibility that dopamine-glutamatergic interactions contribute to Pb's effects.
Cory-Slechta
D A
DA
Department of Neurobiology and Anatomy, University of Rochester, School of Medicine and Dentistry, NY 14642, USA. slechta@envmed.rochester.edu
Garcia-Osuna
M
M
Greenamyre
J T
JT
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects*; D001345:Autoradiography; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D001931:Brain Mapping; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D007855:Lead Poisoning / Q000503:physiopathology*; D008297:Male; D011939:Mental Recall / Q000187:drug effects*; D016202:N-Methylaspartate / Q000493:pharmacokinetics / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000633:toxicity; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D009942:Organometallic Compounds; D016194:Receptors, N-Methyl-D-Aspartate; C069052:CGP 39653; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; C008261:lead acetate