Effect of soman on schedule-controlled behavior and brain acetylcholinesterase in rats

Brezenoff, Henry E.; McGee, John; Hymowitz, Norman

doi:10.1016/0024-3205(85)90110-9

Cited by 19 publications

(1 citation statement)

References 16 publications

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“…In this context it is interesting to note that the sensitivity of ACh-esterases of different brain regions to OP anti-ChEs also differs, with cortical AChesterase inhibited to the highest degree by soman and striatal ACh-esterase the least (34).…”

Section: Inhibition Of Ach-esterase By Opsmentioning

confidence: 99%

Direct actions of organophosphate anticholinesterases on nicotinic and muscarinic acetylcholine receptors

Bakry

El‐Rashidy

Eldefrawi

et al. 1988

J. Biochem. Toxicol.

163

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Four nerve agents and one therapeutic organophosphate (OP) anticholinesterase (anti-ChE) bind to acetylcholine (ACh) receptors, inhibit or modulate binding of radioactive ligands to these receptors, and modify events regulated by them. The affinity of nicotinic (n) ACh receptors of Torpedo electric organs and most muscarinic (m) ACh receptors of rat brain and N1E-115 neuroblastoma cultures for the OP compounds was usually two to three orders of magnitude lower than concentrations required to inhibit 50% (IC-50) of ACh-esterase activity. However, a small population of m-ACh receptors had an affinity as high as that of ACh-esterase for the OP compound. This population is identified by its high-affinity [3H]-cis-methyldioxolane ([3H]-CD) binding. Although sarin, soman, and tabun had no effect, (O-ethyl S[2-(diisopropylamino)ethyl)] methyl phosphonothionate (VX) and echothiophate inhibited competitively the binding of [3H]-quinuclidinyl benzilate ([3H]-QNB) and [3H]-pirenzepine ([3H]-PZ) to m-ACh receptors. However, VX was more potent than echothiophate in inhibiting this binding and 50-fold more potent in inhibiting carbamylcholine (carb)-stimulated [3H]-cGMP synthesis in N1E-115 neuroblastoma cells--both acting as m receptor antagonist. All five OPs inhibited [3H]-CD binding, with IC-50s of 3, 10, 40, 100, and 800 nM for VX, soman, sarin, echothiophate, and tabun, respectively. The OP anticholinesterases also bound to allosteric sites on the n-ACh receptor (identified by inhibition of [3H]-phencyclidine binding), but some bound as well to the receptor's recognition site (identified by inhibition of [125I]-alpha-bungarotoxin binding). Soman and echothiophate in micromolar concentrations acted as partial agonists of the n-ACh receptor and induced receptor desensitization. On the other hand, VX acted as an open channel blocker of the activated receptor and also enhanced receptor desensitization. It is suggested that the toxicity of OP anticholinesterases may include their action on n-ACh as well as m-ACh receptors if their concentrations in circulation rise above micromolar levels. At nanomolar concentrations their toxicity is due mainly to their inhibition of ACh-esterase. However, at these low concentrations, many OP anticholinesterases (eg, VX and soman) may affect a small population of m-ACh receptors, which have a high affinity for CD. Such effects on m-ACh receptors may play an important role in the toxicity of certain OP compounds.

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Section: Inhibition Of Ach-esterase By Opsmentioning

confidence: 99%

Direct actions of organophosphate anticholinesterases on nicotinic and muscarinic acetylcholine receptors

Bakry

El‐Rashidy

Eldefrawi

et al. 1988

J. Biochem. Toxicol.

163

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Physiological Compensation for Toxic Actions of Organophosphate Insecticides

Chambers

1989

Insecticide Action

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Receptor-mediated presynaptic facilitation of quantal release of acetylcholine induced by pralidoxime inAplysia

et al. 1990

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1. Possible interactions of contrathion (pralidoxime sulfomethylate), a reactivator of phosphorylated acetylcholinesterase (AChE), with the regulation of cholinergic transmission were investigated on an identified synapse in the buccal ganglion of Aplysia californica. 2. Transmitter release was evoked either by a presynaptic action potential or, under voltage clamp, by a long depolarization of the presynaptic cell. At concentrations higher than 10(-5) M, bath-applied contrathion decreased the amplitude of miniature postsynaptic currents and increased their decay time. At the same time, the quantal release of ACh was transiently facilitated. The facilitatory effect of contrathion was prevented by tubocurarine but not by atropine. Because in this preparation, these drugs block, respectively, the presynaptic nicotinic-like and muscarinic-like receptors involved in positive and negative feedback of ACh release, we proposed that contrathion activates presynaptic nicotinic-like receptors. 3. Differential desensitization of the presynaptic receptors is proposed to explain the transience of the facilitatory action of contrathion on ACh release. 4. The complexity of the synaptic action of contrathion raises the possibility that its therapeutic effects in AChE poisonings are not limited to AChE reactivation.

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Effect of soman on schedule-controlled behavior and brain acetylcholinesterase in rats

Cited by 19 publications

References 16 publications

Direct actions of organophosphate anticholinesterases on nicotinic and muscarinic acetylcholine receptors

Direct actions of organophosphate anticholinesterases on nicotinic and muscarinic acetylcholine receptors

Physiological Compensation for Toxic Actions of Organophosphate Insecticides

Receptor-mediated presynaptic facilitation of quantal release of acetylcholine induced by pralidoxime inAplysia

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