Paraoxon: cholinesterase-independent stimulation of transmitter release and selective block of ligand-gated ion channels in cultured hippocampal neurons.
Paraoxon (O,O-diethyl O-p-nitrophenyl phosphate) is the neurotoxic metabolite of the insecticide parathion (O,O-diethyl O-p-nitrophenyl phosphorothioate). The effects of organophosphorus compounds on peripheral synapses have been attributed to inhibition of cholinesterase and to direct actions on muscarinic and nicotinic receptors, but less is known about the actions of organophosphorus compounds, including paraoxon, in the central nervous system. We investigated initially the effects of paraoxon on spontaneous transmitter release by recording miniature postsynaptic currents (MPSCs) from cultured rat hippocampal neurons using the whole-cell mode of the patch-clamp technique. Paraoxon (0.3 microM) in the presence of tetrodotoxin (0.3 microM) and atropine (1 microM) caused a significant increase in the frequency of gamma-aminobutyric acid- and glutamate-mediated MPSCs, but did not change the peak amplitudes or decay-time constants of these MPSCs. In contrast, application of nicotinic agonists or antagonists did not change the MPSC frequency. The presynaptic effect of paraoxon shown here was not mediated by actions on muscarinic or nicotinic receptors, or by elevated acetylcholine levels secondary to inhibition of cholinesterase. In addition, agonists were applied to assess the postsynaptic effects of paraoxon on excitatory and inhibitory amino acid receptors. Paraoxon (30 microM-1 mM) blocked the ion channels of glycine, gamma-aminobutyric acidA, N-methyl-D-aspartic acid and nicotinic acetylcholine receptors, but not the ion channels of kalnate- and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. The combined effects of paraoxon on spontaneous transmitter release and on the functions of several ligand-gated receptors may constitute mechanisms relevant to the neurotoxicity of paraoxon.
Rocha
E S
ES
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, USA.
Swanson
K L
KL
Aracava
Y
Y
Goolsby
J E
JE
Maelicke
A
A
Albuquerque
E X
EX
D000818:Animals; D002478:Cells, Cultured; D002802:Cholinesterases / Q000378:metabolism; D004553:Electric Conductivity; D005971:Glutamates / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010261:Paraoxon / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects; D017470:Receptors, Glutamate / Q000187:drug effects; D018009:Receptors, Glycine / Q000187:drug effects; D018092:Kainic Acid Receptors / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects; D013570:Synaptic Membranes / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002802:Cholinesterases; D005971:Glutamates; D005998:Glycine; D018733:Nicotinic Antagonists; D010261:Paraoxon; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018009:Receptors, Glycine; D018092:Kainic Acid Receptors; D011978:Receptors, Nicotinic; D005680:gamma-Aminobutyric Acid