Muscarinic Receptor Dysfunction Induced by Exposure to Low Levels of Soman Vapor

Abstract

In the eye, it has been previously reported that exposure to a cholinesterase inhibitor results in a reduced miotic response following prolonged exposure and a decreased miotic response to the cholinergic agonists. However, no studies exist that characterize the effect of a single low-level vapor exposure to a nerve agent on parasympathetic function in the eye or determine the threshold dose for such an effect. The present study investigated the hypotheses that a single low-level exposure to soman vapor would result in dysfunction of the parasympathetic pathway mediating the pupillary light reflex resulting from a loss of muscarinic receptor function on the pupillary sphincter muscle. Adult male rats were exposed to soman vapor in a whole-body dynamic airflow exposure chamber. Rats exposed to low levels of soman vapor dose-dependently developed miosis (threshold dose between 4.1 and 6.1 mg-min/m3). Pupil size returned to preexposure levels within 48 h due to desensitization of pupillary muscarinic receptors, as assessed by the pupillary response to the muscarinic agonist oxotremorine. An attenuated pupillary light reflex was also present in miotic animals (threshold dose near 6.1 mg-min/m3). While pupil size recovers within 48 h, other measures of pupillary function, including the light reflex, acetylcholinesterase activity, and muscarinic receptor responsiveness, did not return to normal for up to 10 days postexposure. Recovery of the light reflex coincided with the recovery of pupillary muscarinic receptor function, suggesting that the attenuation of the light reflex was due to receptor desensitization.

Pretreatment of Guinea Pigs with Galantamine Prevents Immediate and Delayed Effects of Soman on Inhibitory Synaptic Transmission in the Hippocampus

“…Because AChE activity remains significantly inhibited by 24 h after an exposure of guinea pigs to 1ϫLD 50 soman (Lintern et al, 1998), the low frequency of IPSCs could be explained by ACh-induced desensitization of mAChRs and nAChRs on CA1 interneurons. Longlasting loss of mAChR function caused by desensitization by excess ACh has been observed on the papillary sphincter muscle of rats exposed to low levels of soman (Dabisch et al, 2007). In addition, the decreased ␣7 nAChR activity recorded from CA1 stratum oriens interneurons at 24 h after an acute exposure of guinea pigs to 1ϫLD 50 soman has been attributed to receptor desensitization by accumulated ACh .…”

Galantamine prevents long-lasting suppression of excitatory synaptic transmission in CA1 pyramidal neurons of soman-challenged guinea pigs

“…Dabisch et al (2007) reported that exposure of rats to soman causes mAChR desensitization that outlasts AChE inhibition in the eye. Long-lasting desensitization of M1 mAChRs in the guinea pig hippocampus could well explain the persistent suppression of glutamatergic transmission in CA1 pyramidal neurons of soman-exposed guinea pigs, because activation of these mAChRs has been shown to increase the frequency of EPSCs in CA1 pyramidal neurons (Bouron and Reuter, 1997).…”

Efficacy assessment of a combined anticholinergic and oxime treatment against topical sarin‐induced miosis and visual impairment in rats

“…Despite the prolonged ChE inhibition (Lund‐Karlsen and Fonnum, ) and the subsequent hypercholinergic process (Grob and Harvey, ; Mattio et al ., ), an iris papillary muscle relaxation is observed in animals at the first hours following ocular OP exposure (Dabisch et al ., ; Gore et al ., ). This mechanism may be explained by the desensitization of the local muscarinic receptors (Dabisch et al ., ). Previously, it had been reported in animals that topical oxime treatment following OP ocular exposure led to a significant re‐activation of the ChE enzyme in a few hours, accelerating pupil widening (Lund‐Karlsen and Fonnum, ).…”

“…following ocular OP exposure (Dabisch et al, 2007;Gore et al, 2012). This mechanism may be explained by the desensitization of the local muscarinic receptors (Dabisch et al, 2007).…”