Changes in presynaptic release of acetylcholine during development of tolerance to the anticholinesterase, DFP

Abstract

The rat myenteric plexus was used as a peripheral model for studying muscarinic modulation of acetylcholine (ACh) release from presynaptic muscarinic neurons during development of tolerance to the anticholinesterase agent, diisopropylfluorophosphate (DFP). DFP in arachis oil was administered subcutaneously to intact animals according to both acute and chronic regimens, with arachis oil injections serving as controls. Post-mortem analyses showed that the mean AChE activity level in whole brain was reduced under all DFP conditions to 18.0 +/- 1.4% when compared with the control level. After 10 days of DFP treatment, the AChE level was 22.3 +/- 2.1% of control in the myenteric plexus. There were no significant differences among the treatment groups in resting ACh release. Release evoked by electrical stimulation (difference between stimulated and resting release) in the absence of atropine, i.e., "basal rate," for strips taken at various times after a single injection of DFP did not differ from that for strips from animals receiving arachis oil only. However, basal release for strips from chronically treated subjects was significantly greater than that of controls (p less than 10(-3), although not different from each other. Analysis of variance (ANOVA) for repeated measures showed that there existed a highly significant atropine dependency in strips from all treatments when they were stimulated in concentrations of atropine from 10(-9) to 10(-5) M (p less than 10(-10). Further analyses established that the increases in rates of evoked ACh release as concentrations of atropine increased were similar for strips from chronically treated DFP and arachis oil animals.(ABSTRACT TRUNCATED AT 250 WORDS)