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.