EFFECTS OF METRIFONATE, ITS TRANSFORMATION PRODUCT DICHLORVOS, AND OTHER ORGANOPHOSPHORUS AND REFERENCE CHOLINESTERASE-INHIBITORS ON MORRISWATER ESCAPE BEHAVIOR IN YOUNG-ADULT RATS

Metrifonate is currently under development as a putative cholinergic A lzheimer therapeutic, because it is a prodrug of the long-acting organ ophosphate cholinesterase (ChE) inhibitor dichlorvos. The aim of this study was to examine whether the transformation of metrifonate to dich lorvos and the resulting indirect inhibition of ChE are required for i ts previously documented cognition-enhancing properties in a standard Morris water escape task with intact rats. This was done by investigat ing whether the cognition-enhancing effects of metrifonate could be mi micked by dichlorvos, by the organophosphorus compounds diisopropylflu orophosphate and paraoxon or by structurally unrelated reference ChE i nhibitors, such as tetrahydroaminoacridine, E2020, and physostigmine. Metrifonate, and to a lesser degree dichlorvos, and diisopropylfluorop hosphate improved the acquisition of the water escape task, whereas pa raoxon did not. The dose-response curves of the organophosphorus compo unds were bell-shaped with apparent optimal doses of 10 to 30 mg/kg fo r metrifonate and 0.03 mg/kg for both dichlorvos and diisopropylfluoro phosphate. The reference compounds E2020, physostigmine and tetrahydro aminoacridine did not affect learning and memory in the young-adult ra t at doses that had previously been reported to mediate cognitive enha ncement in deficiency models. Our results question whether the effect of metrifonate is mediated by inhibition of ChE alone and suggest the involvement of an additional, as yet unknown, mechanism of action.