Cholinolytic antagonism to the disruptive effects of oral low doses of pyridostigmine on simple discrimination performance in rats.

We have previously reported that acute oral administration of low doses (less than or equal to 12 mg/kg) of pyridostigmine bromide (PYR) to rats resulted in a dose-dependent decrement in reinforcement rate under two different multiple schedules of response-produced water presentation, which involved motivational dysfunction rather than motor impairment and alterations in visual perception. The purpose of the present investigation was to examine further if the anticipated operant behavioral deficits of PYR are mediated by central and/or peripheral cholinergic mechanisms. Lever-press responses of male Sprague-Dawley rats were maintained under a multiple fixed-ratio GO/differential-reinforcement-of-low-rate NO GO, brightness discrimination, schedule of water reinforcement. The effects of the muscarinic antagonists atropine (ATR) and methylatropine (MAT), both at doses of 0.25, 0.5 and 1.0 mg/kg (SC), against a single oral low dose of PYR (12 mg/kg)-induced behavioral disruption were compared. ATR partially antagonized the reinforcement loss of PYR with concomitant dose-related increases in nonreinforced responses, whereas MAT completely antagonized the reinforcement loss without affecting the frequency of nonreinforced responses. These results suggest that in rats, the debilitating effects of oral PYR on operant behavior are primarily due to the stimulation of peripheral muscarinic receptors via its anticholinesterase activity. The increments of nonreinforced responses observed after coadministration of PYR with ATR may reflect a central, excitatory action of ATR which could affect the discrimination performance. The present results have practical implications for the clinical utilization of PYR in combination with the peripherally active muscarinic antagonist in situations where optimal performance is required.