Selective blockade of NMDA-activated channel currents may be implicated in learning deficits caused by lead.
The effect of Pb2+ on glutamate receptor activity in rat hippocampal neurons was investigated with a view of explaining the cognitive and learning deficits produced by this heavy metal. Pb2+ (2.5-50 microM) selectively inhibited N-methyl-D-aspartate (NMDA)-induced whole-cell and single-channel currents in a concentration-dependent but voltage-independent manner, without significantly altering currents induced by either quisqualate or kainate. The frequency of NMDA-induced channel activation was decreased by Pb2+. Neither glycine (10-100 microM), nor Ca2+ (10 mM) reversed the effect of Pb2+. Pb2+ also inhibited the [3H]MK-801 binding to rat hippocampal membranes in vitro. The elucidation of the actions of Pb2+ on the NMDA receptor ion channel complex provides important insights into the clinical and toxic effects of this cation.
Alkondon
M
M
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201.
Costa
A C
AC
Radhakrishnan
V
V
Aronstam
R S
RS
Albuquerque
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EX
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D003986:Dibenzocycloheptenes / Q000378:metabolism; D016291:Dizocilpine Maleate; D004553:Electric Conductivity; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007473:Ion Channels / Q000187:drug effects* / Q000502:physiology; D007608:Kainic Acid / Q000494:pharmacology; D007854:Lead / Q000494:pharmacology* / Q000633:toxicity; D007859:Learning Disabilities / Q000139:chemically induced*; D008297:Male; D016202:N-Methylaspartate; D010069:Oxadiazoles / Q000494:pharmacology; D016318:Quisqualic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology
D003986:Dibenzocycloheptenes; D007473:Ion Channels; D010069:Oxadiazoles; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D007854:Lead; D001224:Aspartic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D016318:Quisqualic Acid; D007608:Kainic Acid; D002118:Calcium; D005998:Glycine