Effects of antimuscarinic antiparkinsonian drugs on brightness discrimination performance in rats

Abstract

Biperiden (BPR) and trihexyphenidyl (THP), the current antimuscarinic drugs of choice in the management of parkinsonism, have been shown to exert anticonvulsant effects induced by poisoning by the organophosphorus compound soman. The present study was undertaken to evaluate the effects of these drugs on performance of a simple light-intensity discrimination task in rats under a tandem schedule of fixed-ratio (FR) reward/ differential-reinforcement-of-low-rate (DRL) nonreward contingencies, for water reinforcement in 2-h experimental sessions. Both BPR (0.125–2.0 mg/kg, SC) and THP (0.25–8.0 mg/kg, SC) in general decreased overall reinforcement rates in a similar dose dependent and parallel manner, concurrent with increased overall nonreinforced responses in an inverted U-shaped dose-response relationship. Lower doses of BPR (0.125–0.5 mg/kg) and and THP (0.25–2.0 mg/kg) produced a moderate reduction in reinforcement (>−50% of baseline controls), which was correlated well with increases in nonreinforced responses emitted, whereas, higher doses of BPR (> 0.5 mg/kg) and TPH (>−2.0 mg/kg) markedly decreased reinforcements, which mainly resulted from the pausing of responding in the presence of stereotyped behavior. The behavioral disruption induced by BPR was much more rapid than that induced by THP. The ED 50 values (0.6 mg/kg vs. 1.3 mg/kg, respectively) and parallel dose-effect curves suggest that these drugs have similar efficacy, and that BPR is about twice as potent as THP, a ranking that corresponds with their binding affinity at M-1 muscarinic acetylcholine receptors in rat cerebral cortex. Based on the similarity between the anticonvulsant doses of these drugs and the maximal doses that in this study did not disrupt operant responses (0.125 mg/kg vs. 0.25 mg/kg, respectively), it is suggested that both drugs may be useful in protection against seizures produced by the cholinesterase inhibitor soman. Overall, these results suggest that this multiple schedule operant contingency may have promise as a behavioral model to identify the therapeutic or toxic potentials of centrally acting antimuscarinic antiparkinsonian drugs based on their congnitive side effects.