A dose-response analysis of the behavioral effects of (+)MK-801 in guinea pig: comparison with CPP

Abstract

The noncompetitive N-methyl-D-aspartate (NMDA) antagonist, dizocilpine maleate {(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5, 10-imine maleate} [(+)MK-801], has attracted considerable interest because of its potential use as an anticonvulsant and neuroprotectant. However, its cognitive side effects in humans have limited its use in human pharmacotherapy. Although the behavioral effects of (+)MK-801 have been documented in mouse, rat, pigeon, and rhesus monkey, there are no available data on its effects in guinea pig. The objective of this study was to conduct a dose-response analysis of the effects of (+)MK-801 on stereotyped behavior, ataxia, locomotor activity, and righting reflex latency in guinea pig. In the dose range used (0.0625-0.5 mg/kg, IP), we found no significant differences between (+)MK-801 and vehicle in terms of stereotyped behavior and locomotor activity; however, at higher doses, (+)MK-801 caused significant ataxia and impairment of the righting reflex. By comparison, the competitive NMDA receptor antagonist, 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP,5 mg/kg, IP), produced neither stereotyped behavior nor impairment of the righting reflex; at higher doses (10 mg/kg, IP), it produced only ataxia and an increase in locomotor activity.