Blockade of hippocampal long-term potentiation following soman pretreatment in the rat.

One of the most potent toxins known is the cholinesterase inhibitor, soman, which produces severe convulsions and cell loss in the central nervous system. In these experiments the effect of multiple low doses of soman on the acquisition and maintenance of long-term potentiation (LTP) was determined in rats. LTP is a form of synaptic plasticity that has been studied as a cellular substrate for learning and memory mechanisms. Under urethane anesthesia, electrodes were positioned in the dentate gyrus for recording evoked potentials before and after tetanic stimulation of the perforant path. LTP levels were greatly reduced in rats recovering from convulsion-inducing soman treatment. Rats exposed to similar amounts of soman, but not displaying convulsions, also displayed reduced levels of LTP. The responses recorded from these animals were highly variable, ranging from control levels of potentiation to no LTP. The variability could be attributed to some animals having convulsions that were not detected before surgery or to other interanimal differences in the degree of soman-induced toxicity. The long range goal of the experiments presented here is to develop a better rodent model for studying soman-induced functional changes in the CNS that can be detected prior to the gross morphological changes.

Efficacy of physostigmine as a pretreatment for organophosphate poisoning.

Continuous administration of the carbamate physostigmine, producing approximately 40% serum cholinesterase (ChE) inhibition, provides significant protection against the lethal effects of the organophosphorous nerve agent pinacolyl methylphosphonofluoridate (soman). Rats pretreated with physostigmine were also protected against the development of cholinergic symptoms and loss of body weight. Soman and physostigmine both inhibit ChE, yet animals pretreated with physostigmine exhibited less ChE inhibition in serum and brain than did animals exposed to soman alone. In addition, there did not appear to be any additive effect of presenting both anticholinesterases simultaneously. To further examine the effectiveness of physostigmine, we compared the results of this study with previously collected pyridostigmine data from our laboratory. This comparison indicates that physostigmine is more effective than pyridostigmine in protecting against the detrimental effects of soman.

Behavioral toxicity of anticholinesterases in primates: chronic pyridostigmine and soman interactions.

Dose rates for continuous infusion of pyridostigmine bromide required to inhibit 30% and 60% of normal serum cholinesterase activity in rhesus monkeys were determined. The effects of continuous pyridostigmine infusion at these dose-rates on the behavioral toxicity of 5 daily repeated low-dose exposures to a toxic organophosphate (soman) were determined not be deleterious; in fact, they were slightly (and variably) protective. Relative to controls (5-day soman ED50 = 0.89 micrograms/kg/day), pyridostigmine infusions producing 30% and 60% inhibition produced 5-day ED50s of 1.25 and 1.11 micrograms/kg/day, respectively. Variability in response to the pyridostigmine-soman combinations appeared to be greater than in response to daily soman exposure without pyridostigmine infusion.

Toxic interactions between repeated soman and chronic pyridostigmine in rodents.

These experiments examined the interactions of pyridostigmine, a reversible, peripherally acting anticholinesterase, with soman, an irreversible, peripherally and centrally acting anticholinesterase. Lethality, weight change, symptoms, and serum cholinesterase inhibition were determined following five daily injections of soman in rodents implanted with osmotic pumps containing two concentrations of pyridostigmine or vehicle. Concurrent exposure to both anticholinesterases had no effect on any measure at pyridostigmine-induced cholinesterase inhibition levels of 35% or 70% compared to controls. These results emphasize the safety of pyridostigmine as a pretreatment against organophosphate toxicity.

Premature excess release from the Alzet osmotic pump.

This paper alerts investigators to the possibility of an excessive early release from the Alzet osmotic pump. In this research, rats were implanted with 7-day minipumps (model 2001) containing 24 mg/kg/day pyridostigmine, and blood samples were taken at intervals from 5 to 60 min after implantation. All samples showed that blood serum cholinesterase activity was markedly depressed as compared with those of controls. This finding demonstrated that animals were receiving the drug well before the pump's 4- to 6-hr start-up transient period. In a separate study, dye filled pumps were monitored for release when dropped into distilled water at 24 degrees C or 37 degrees C. The pump in the 37 degrees C water released approximately 5% of its contents within 30 sec of submersion, while the pump in the 24 degrees C water released virtually no dye. The early release appears to have been caused by expansion of the pump's contents when the pump, at room temperature, was implanted in the warmer animal.