Effects of cholinesterase inhibitors on a two-component chained schedule performance in rats

The acetylcholinesterase (AChE) inhibitors physostigmine (PHY), tacrine (THA), and heptylphysostigmine (HEP) have been evaluated as potential therapeutics for treatment of Alzheimer's disease (AD) and as prophylactics against organophosphate (OP) poisoning. The above medical applications are based upon the neurochemical principles of elevation of transient levels of acetylcholine (ACh) in brain and reversible inhibition of AChE in blood and brain, respectively. The present study was undertaken to evaluate the effects of these drugs on performance of a two-component chained schedule of differential-reinforcement-of-high-rate (DRH) reward/differential-reinforcement-of-low-rate (DRL) nonreward contingencies, for water reinforcement in 2-h experimental sessions in rats. Both PHY (0.031-0.25 mg/kg, SC) and HEP (0.625-10.0 mg/kg, SC) decreased overall reinforcement rate and nonreinforced response in a dose-related and parallel manner, whereas THA (0.625-5.0 mg/kg) decreased the overall reinforcement rate in a dose-related manner, but did not significantly affect nonreinforced response. The least significant doses of PHY (0.625 mg/kg), THA (1.25 mg/kg), and HEP (1. 25 mg/kg) on the behavioral performance were associated with oral movements and/or muscle fasciculation. Moderate to high doses of these drugs (i.e., PHY >/= 0.624, THA >/= 1.25, and HEP >/= 1.25 mg/kg) produced behavioral suppression, which resulted mostly from the cessation of responding in the presence of cholinergic adverse events. The ED(50) values of the behavioral disruption (as documented by overall reinforcer loss) for PHY, THA, and HEP were 0. 081, 3.87, and 2.89 mg/kg, respectively, and the behavioral-deficit-free (BDF) doses were 0.031, 0.625, and 0.625 mg/kg, respectively. Preclinical data revealed that the BDF doses of both PHY and HEP have moderate inhibition of AChE, which leads to an efficacious elevation of ACh level in the brain, whereas the BDF dose of THA shows no significant AChE inhibition or elevation of brain ACh level; however, they all have cognition enhancing effects at their respective safety doses. The above data suggest that the BDF doses of PHY and HEP may have prophylactic efficacy against OP poisoning, whereas THA may not. The BDF doses of these three drugs are comparable to the maximum tolerated doses in clinical practice, suggesting that the present rat model may have potential value in predicting the clinical safety of AChE inhibitors developed for therapy of AD and prophylaxis against OP poisoning as well.