title: Nanomolar concentrations of lead inhibit glutamatergic and GABAergic transmission in hippocampal neurons.
abstract: To investigate whether lead (Pb2+) affects the tetrodotoxin (TTX)-sensitive release of neurotransmitters, the whole-cell mode of the patch-clamp technique was applied to cultured hippocampal neurons. Pb2+ (>/=10 nM) reversibly blocked the TTX-sensitive release of glutamate and gamma-aminobutyric acid (GABA), as evidenced by the reduction of the amplitude and frequency of glutamate- and GABA-mediated postsynaptic currents (PSCs) evoked by spontaneous neuronal firing. This effect of Pb2+, which occurred 2-3 s after exposure of the neurons to Pb2+-containing external solution, was not related to changes in Na+-channel activity, and was quantified by measurements of changes in the amplitude of PSCs evoked when a 50-micros, 5-V stimulus was applied via a bipolar electrode to a neuron synaptically connected to the neuron under study. With an IC50 of approximately 68 nM, Pb2+ blocked the evoked release of glutamate and GABA. This effect was most likely mediated by Pb2+'s actions on extracellular targets, because there was a very short delay (<3 s) for its onset, and it could be completely reversed by the chelator ethylene diaminetetraacetic acid (EDTA). Given that Pb2+-induced blockade of evoked transmitter release could be reversed by 4-aminopyridine, it is suggested that the effect on release was mediated via the binding of Pb2+ to voltage-gated Ca2+ channels. Thus, it is most likely that the neurotoxic effects of Pb2+ in the mammalian brain involve a decrease of the TTX-sensitive, Ca2+-dependent release of neurotransmitters.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Braga
authors.forename: E F
authors.initials: EF
authors.lastname: Pereira
authors.forename: E X
authors.initials: EX
authors.lastname: Albuquerque
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D007700:Kinetics; D007854:Lead / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D015222:Sodium Channels / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D015761:4-Aminopyridine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D002614:Chelating Agents; D004492:Edetic Acid; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018698:Glutamic Acid; D007854:Lead; D010852:Picrotoxin; D015221:Potassium Channels; D015222:Sodium Channels; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid