In vitro and in vivo effects of lead on specific 3H-MK-801 binding to NMDA-receptors in the brain of mice.
The in vitro and vivo effects of lead on the NMDA-receptors in adult 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 their drinking water for 30 and 90 days. Perinatal exposure was achieved 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 binding studies on homogenates of the forebrain with the non competitive NMDA-antagonist 3H-MK-801. In vitro, complete inhibition of the radioligand binding was found with half maximal inhibiting concentrations (IC50-values) of 19.7 +/- 2.6 microM (SEM) in absence of amino acids and 9.5 +/- 0.9 in presence of glutamate and glycine. These concentrations are in a range which could be achieved in vivo, e.g. the lead content in the forebrain of juvenile mice treated with 1,000 ppm lead was 10.0 +/- 1.8 mumol/kg wet weight. It was speculated that lead binds at the zinc binding site. In the presence of amino acids and divalent cations, such as calcium or magnesium, low lead concentrations lead to a significant increase in receptor affinity. Analysis of the saturation experiments carried out on forebrain homogenates of lead-treated animals showed a slight increase in receptor density of 13 or 15% with an unchanged Kd-value only in the adult animals treated with 100 ppm lead and in absence of stimulating amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)
Schulte
S
S
Institut für Pharmakologie und Toxikologie Fakultät für Klinische Medizin Mannheim, Universität Heidelberg, Germany.
Müller
W E
WE
Friedberg
K D
KD
D000375:Aging / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D007700:Kinetics; D007854:Lead / Q000633:toxicity*; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*; D015032:Zinc / Q000633:toxicity
D016194:Receptors, N-Methyl-D-Aspartate; D007854:Lead; D016291:Dizocilpine Maleate; D015032:Zinc