Studies in our laboratory have demonstrated that alpha 2-adrenergic agonists such as clonidine inhibit acetylcholine synthesis and release. The effect of clonidine is so marked, that pretreatment reduces both the accumulation of brain acetylcholine, and the toxicity caused by cholinesterase inhibitors such as soman. In this study rats were pretreated with regimens which included known protective doses of clonidine or atropine. The dose of soman was adjusted to allow for the 24 hr survival of 50% of the animals in each group. Behavioral toxicity was assessed by observational techniques and by employing an automated animal activity monitor. Clonidine pretreatment resulted in a significant degree of protection from the lethal effects of soman in the rat. In addition, the ability of soman to inhibit normal ongoing behavior as well to elicit the expression of several abnormal behaviors, including convulsive behavior were inhibited by clonidine pretreatment. While clonidine pretreatment resulted in a similar degree of protection as atropine pretreatment against the acute phase of soman toxicity, only clonidine was effective in preventing the expression of chronic behavioral toxic manifestations to soman. Thus, animals pretreated with clonidine exhibited a significantly improved prognosis 24 or 48 hr following soman injection as compared with saline- or atropine-pretreated animals.