Dizocilpine improves beneficial effects of cholinergic antagonists in anticholinesterase-treated mice

Mice were administered anticholinesterase pesticides dichlorvos (DDVP) or methomyl (MET). Both DDVP and MET induced dose-dependent seizures and lethality in mice. The muscarinic antagonist atropine (ATR, 1.8 mg/kg) did not prevent seizures but diminished the lethality induced by DDVP or MET. The nicotinic antagonist mecamylamine (MEC, 1 mg/kg) affected neither DDVP-induced seizures nor DDVP- and MET-induced lethality, but diminished MET-induced seizures. At a higher dose (10 mg/kg), MEC attenuated seizures produced by MET, but not DDVP, and decreased lethality of both anticholinesterases. The N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801, 1 mg/kg) prevented DDVP-, but not MET-induced seizures. MK-801 did not affect DDVP- or MET-induced lethality. Concurrent administration of ATR and MK-801 prevented the occurrence of DDVP- but not MET-induced seizures. MK-801 coadministered with ATR enhanced its protective effect against DDVP- or MET-induced lethality in mice. Coinjection of MEC (at both doses studied) and MK-801 completely prevented seizures produced by both acetylcholinesterase (AChE) inhibitors. Coadministration of MEC (1 mg/kg) and MK-801 protected mice against DDVP or MET lethality. MK-801 administered along with MEC at 10 mg/kg enhanced antilethal effects of the nicotinic antagonist in DDVP- or MET-treated mice. With respect to the mechanism underlying anticholinesterase-induced neurotoxicity, muscarinic and nicotinic, as well as NMDA receptors, seem to play major roles. The results suggest that combined treatment with cholinergic and NMDA antagonists might be beneficial in anticholinesterase-induced poisonings.