Time-dependent changes in the effects of cholinesterase inhibitors on shuttle-box avoidance.

Physostigmine and neostigmine were compared for their effects on shuttle-box avoidance acquisition and retention. Physostigmine impaired acquisition at doses lower than neostigmine. Avoidance performance 1, 7, or 14 days after acquisition was impaired by the administration of 0.4 mg/kg physostigmine or an equimolar dose of neostigmine. The effects of lower doses of physostigmine, but not of neostigmine, were dependent upon the time of original training relative to drug administration and retesting. The results suggest that the peripheral effects of higher doses of cholinesterase inhibitors impair avoidance performance. The effects of lower doses of physostigmine on acquisition and the time-dependent effects on subsequent performance are probably due to the central actions of this drug.