Tolerance to behavioral effects of physostigmine under interval schedules of positive or negative reinforcement.

The present experiments examined whether the rate and type of events maintaining responding help determine physostigmine's behavioral effects. The first two experiments examined the acute and chronic effects of physostigmine, respectively, on lever pressing of rats under variable-interval schedules of food presentation. The third examined the chronic effects of physostigmine on lever pressing under random-interval schedules of shock avoidance. Three different variable intervals (18, 56, and 180 s) and two different random intervals (20 and 60 s) were studied, each associated with a distinctive stimulus. Baseline rates of responding were directly related to the scheduled rate of food delivery or shock avoidance. Acute administration of 0.154-1.233 mumol/kg (0.1-0.8 mg/kg) physostigmine sulfate produced monotonic decreases in overall response rate under all schedules of food presentation. Acute effects (per cent of control response rate) did not differ systematically under the various interval values. Large doses (i.e., 0.4 or 0.8 mg/kg) suppressed the rate of food delivery as well. When initially administered, 0.967 mumol/kg (0.4 mg/kg) physostigmine salicylate also suppressed avoidance response rates and per cent shocks avoided. Tolerance developed to the effects of this dose of physostigmine salicylate on pellet or shock-avoidance frequency more rapidly than to effects on overall response rate. Tolerance to the latter developed only very gradually and could in the case of shock-avoidance response rates be considered partial at best. Tolerance was not affected by the scheduled rate of food or shock presentation. Blood acetylcholinesterase levels showed no recovery during chronic physostigmine. Tolerance is discussed in terms of the reinforcement-loss hypothesis.