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The role of cholinergic and non-cholinergic mechanisms in mediating organophosphate cholinesterase (ChE) inhibitor-induced elevations in choline levels in brain was investigated. The nerve agents soman and sarin, when administered to rats at doses greater than the IC50 for acetylChE inhibition, significantly increased the levels of choline and acetylcholine in both the striatum and hippocampus. The elevation in choline levels was evident 1 hr after injection with a maximal increase at 2 hr. Levels of choline returned to control by 4 hr. In contrast, the administration of diisopropyl phosphorofluoridate at doses greater than the IC50 for acetylChE inhibition increased the levels of acetylcholine, but did not alter the concentration of choline during the first 3 hr. Between 4 and 24 hr after injection, however, a significant decrease in choline levels was apparent. This effect persisted for 48 hr. When rats were pretreated with the anticonvulsant diazepam, the sarin- and soman-induced increases in choline levels were attenuated significantly. Results indicate that the organophosphates differentially alter the levels of choline in brain and suggest that the effect of soman and sarin to elevate choline levels is not a reflection of excessive cholinergic activity, but rather may be a consequence of the excitotoxic actions of these compounds.