IN-VITRO AND IN-VIVO EFFECTS OF LEAD ON SPECIFIC H-3 MK-801 BINDING TO NMDA-RECEPTORS IN THE BRAIN OF MICE

The in vitro and in vivo effects of lead on the NMDA-receptors in adul t and juvenile mice were studied by means of receptor binding assays. Adult female NMRI-mice received 100 and 1,000 ppm lead as nitrate in t heir drinking water for 30 and 90 days. Perinatal exposure was achieve d by treating gestating mice from the 5th day post conception with 0, 100 or 1,000 ppm lead in their drinking water. Characterization of the NMDA (N-methyl-D-aspartate)-receptor was carried out ex vivo using bi nding studies on homogenates of the forebrain with the non competitive NMDA-antagonist H-3-MK-801. In vitro, complete inhibition of the radi oligand binding was found with half maximal inhibiting concentrations (IC50-values) of 19.7 +/- 2.6 mu M (SEM) in absence of amino acids and 9.5 +/- 0.9 in presence of glutamate and glycine. These concentration s are in a range which could be achieved in vivo, e.g. the lead conten t in the forebrain of juvenile mice treated with 1,000 ppm lead was 10 .0 +/- 1.8 mu mol/kg wet weight. It was speculated that lead binds at the zinc binding site. In the presence of amino acids and divalent cat ions, such as calcium or magnesium, low lead concentrations led to a s ignificant increase in receptor affinity. Analysis of the saturation e xperiments carried out on forebrain homogenates of lead-treated animal s showed a slight increase in receptor density of 13 or 15% with an un changed Kd-value only in the adult animals treated with 100 ppm lead a nd in absence of stimulating amino acids. No changes in receptor affin ity or receptor density were found in the neonatally lead-exposed mice . In summary, modulation of the H-3-MK-801 binding by low concentratio ns of lead which was demonstrated in vitro indicates an altered functi onal state of the calcium ionophore within the NMDA-receptor complex. This is possibly one mechanism through which lead affects glutamatergi c neurotransmission in vivo. A chronic exposure to lead was not associ ated with adaptive changes in NMDA-receptor density in the forebrain o f the mouse. (C) 1995 Intox Press, Inc.