Low concentrations of the organophosphate VX affect spontaneous and evoked transmitter release from hippocampal neurons: toxicological relevance of cholinesterase-independent actions.
In the present study, the patch-clamp technique was applied to cultured hippocampal neurons to evaluate the effects of the nerve agent VX on evoked and spontaneous postsynaptic currents mediated by gamma-aminobutyric acid (GABA) and glutamate. At 0.01 nM, VX reduced the amplitude of evoked GABAergic currents, and only at concentrations >1 nM did it decrease the amplitude of evoked glutamatergic currents. The effect of VX on GABAergic currents, which was partially reversible upon washing of the neurons with VX-free external solution, could be prevented by the muscarinic antagonist atropine. In contrast, the effect of VX on glutamatergic currents, which was not reversible upon washing, appears to be related to the VX-induced reduction of the amplitude and frequency of repetitively firing by action potentials. In the presence of the Na(+)-channel blocker tetrodotoxin (TTX), VX (>/=10 nM) increased the frequency of GABA- and glutamate-mediated miniature postsynaptic currents (MPSCs). This effect of VX was unrelated to cholinesterase inhibition and was Ca(2+) dependent. The lack of effect of VX on MPSC kinetics indicates that VX-induced alterations of evoked and spontaneous currents are exclusively due to alterations of the transmitter release processes. The ability of VX to affect transmitter release in the brain may underlie some of its neurotoxic effects and may provide the basis for the development of therapeutic countermeasures to treat and/or prevent VX-induced neurotoxicity.
Rocha
E S
ES
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA.
Santos
M D
MD
Chebabo
S R
SR
Aracava
Y
Y
Albuquerque
E X
EX
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002802:Cholinesterases / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005071:Evoked Potentials / Q000187:drug effects*; D005260:Female; D005971:Glutamates / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D001285:Atropine; D002118:Calcium; D002802:Cholinesterases; D005971:Glutamates; D009943:Organophosphorus Compounds; D009946:Organothiophosphorus Compounds; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; C009680:VX-agent