Long-term behavioral and learning abnormalities produced by the irreversible cholinesterase inhibitor soman: effect of a standard pretreatment regimen and clonidine.

Previous studies in this laboratory have demonstrated that the alpha 2-adrenergic agonist clonidine and related drugs can offer significant protection against both the acute and chronic toxicity to soman administration in rats and mice. The purpose of this study was to determine whether addition of clonidine to a standard pretreatment protective regimen against soman toxicity could offer added protection or benefit. The standard regimen employed was a mixture of physostigmine salicylate (150 micrograms/kg) and artane (trihexyphenidyl hydrochloride 2 mg/kg). Rats were randomly assigned to one of 4 experimental groups: (1) those receiving i.m. sterile saline injection followed 30 min later by s.c. saline injection (normal controls); (2) saline, i.m. followed 30 min later by one of several doses (60-110 micrograms/kg of soman, s.c.; (3) saline, i.m., followed 10 min later by the standard pretreatment regimen i.m., followed by one of several doses of soman (160-300 micrograms/kg), s.c.; and (4) clonidine hydrochloride (1 mg/kg) i.m., followed 10 min later by the pretreatment regimen, followed 30 min later by soman. All animals were examined acutely and survivors were examined over a 3-week period following soman administration. The following observations were made: (1) Addition of clonidine to the standard pretreatment regimen did not enhance survival rate over the standard regimen alone (unless the clonidine was administered after the regimen). (2) Of the acutely toxic behavioral signs promoted by soman, clonidine addition to the standard regimen was of benefit only in reducing soman-induced tremor. (3) Addition of clonidine to the standard regimen appeared to hasten the return to normal motor behavior after soman; however, all groups exhibited normal motor behavior in 9 days. (4) Despite apparent normal motor behavior, soman-treated animals exhibited a marked performance deficit in the passive avoidance parameter 3 weeks after injection. The standard regimen partially preserved this effect; addition of clonidine to the standard regimen completely reversed the effect. These results indicate that clonidine provides a measure of protection against chronic behavioral deficits caused by soman intoxication.