PARAOXON - CHOLINESTERASE-INDEPENDENT STIMULATION OF TRANSMITTER RELEASE AND SELECTIVE BLOCK OF LIGAND-GATED ION CHANNELS IN CULTURED HIPPOCAMPAL-NEURONS
Es. Rocha et al., PARAOXON - CHOLINESTERASE-INDEPENDENT STIMULATION OF TRANSMITTER RELEASE AND SELECTIVE BLOCK OF LIGAND-GATED ION CHANNELS IN CULTURED HIPPOCAMPAL-NEURONS, The Journal of pharmacology and experimental therapeutics, 278(3), 1996, pp. 1175-1187
Paraoxon (O,O-diethyl O-p-nitrophenyl phosphate) is the neurotoxic met
abolite of the insecticide parathion (O,O-diethyl O-p-nitrophenyl phos
phorothioate). 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 know
n 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 us
ing the whole-cell mode of the patch-clamp technique. Paraoxon (0.3 mu
M) in the presence of tetrodotoxin (0.3 mu M) and atropine (1 mu M) c
aused a significant increase in the frequency of gamma-aminobutyric ac
id- and glutamate-mediated MPSCs, but did not change the peak amplitud
es 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 acti
ons on muscarinic or nicotinic receptors, or by elevated acetylcholine
levels secondary to inhibition of cholinesterase. In addition, agonis
ts were applied to assess the postsynaptic effects of paraoxon on exci
tatory and inhibitory amino acid receptors. Paraoxon (30 mu M-1 mM) bl
ocked the ion channels of glycine, gamma-aminobutyric acid(A), N-methy
l-D-aspartic acid and nicotinic acetylcholine receptors, but not the i
on channels of kainate- and lpha-amino-3-hydroxy-5-methyl-4-isoxazolep
ropionic acid-type glutamate receptors. The combined effects of paraox
on on spontaneous transmitter release and on the functions of several
ligand-gated receptors may constitute mechanisms relevant to the neuro
toxicity of paraoxon.